Emerging kinase inhibitors for the treatment of pancreatic ductal adenocarcinoma

References

• Surveillance Epidemiology and End Results (SEER). Cancer Stat Facts: Pancreatic Cancer. (MD). cancer statistics/reports on cancer/ cancer stat facts: pancreatic cancer 2022. Bethesda: Program: U.S. Department of Health and Human Services, N.I.o.H., National Cancer Institute; 2022.
   Google Scholar
• Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–2921.
   PubMed Web of Science ®Google Scholar
• Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33.
   PubMed Web of Science ®Google Scholar
• Ma J, Jemal A. The rise and fall of cancer mortality in the USA: why does pancreatic cancer not follow the trend? Future Oncol. 2013;9(7):917–919.
   PubMed Web of Science ®Google Scholar
• Park W, Chawla A, O’Reilly EM. Pancreatic Cancer: a Review. JAMA. 2021;326(9):851–862.
   PubMed Web of Science ®Google Scholar
• Blackford AL, Canto MI, Klein AP, et al. Recent trends in the incidence and survival of stage 1A pancreatic cancer: a surveillance, epidemiology, and end results analysis. J Natl Cancer Inst. 2020;112(11):1162–1169.
   PubMedGoogle Scholar
• Kardosh A, Lichtensztajn DY, Gubens MA, et al. Long-term survivors of pancreatic cancer: a California population-based study. Pancreas. 2018;47(8):958–966.
   PubMed Web of Science ®Google Scholar
• Bauer MR, Bright EE, MacDonald JJ, et al. Quality of life in patients with pancreatic cancer and their caregivers: a systematic review. Pancreas. 2018;47(4):368–375.
   PubMed Web of Science ®Google Scholar
• Zabora J, BrintzenhofeSzoc K, Curbow B, et al. The prevalence of psychological distress by cancer site. Psychooncology. 2001;10(1):19–28.
   PubMed Web of Science ®Google Scholar
• Beesley VL, Wockner LF, O‘Rourke P, et al. Risk factors for current and future unmet supportive care needs of people with pancreatic cancer. A longitudinal study. Support Care Cancer. 2016;24(8):3589–3599.
   PubMed Web of Science ®Google Scholar
• Nakchbandi IA, Lohr JM. Coagulation, anticoagulation and pancreatic carcinoma. Nat Clin Pract Gastroenterol Hepatol. 2008;5(8):445–455.
   PubMedGoogle Scholar
• Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19): 1817–1825.
   PubMed Web of Science ®Google Scholar
• Burris HA, Moore MJ, Andersen J. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 3rd, et al. 1997;15(6):2403–2413.
   PubMed Web of Science ®Google Scholar
• Von Hoff DD, Ervin T, Arena FP, et al., Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–1703.
   PubMed Web of Science ®Google Scholar
• Wang-Gillam A, Li C-P, Bodoky G, et al., Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018): 545–557.
   PubMed Web of Science ®Google Scholar
• Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the national cancer institute of canada clinical trials group. J Clin Oncol. 2007;25(15):1960–1966.
   PubMed Web of Science ®Google Scholar
• Shin S, Park CM, Kwon H. Erlotinib plus gemcitabine versus gemcitabine for pancreatic cancer: real-world analysis of Korean national database. BMC Cancer. 2016;16:443.
   PubMed Web of Science ®Google Scholar
• Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–2520.
   PubMed Web of Science ®Google Scholar
• Boyiadzis MM, Kirkwood JM, Marshall JL, et al. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J Immunother Cancer. 2018;6(1):35.
   PubMedGoogle Scholar
• Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020;38(1):1–10.
   PubMed Web of Science ®Google Scholar
• Luchini C, Brosens LAA, Wood LD, et al. Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications. Gut. 2021;70(1):148–156.
   PubMed Web of Science ®Google Scholar
• Golan T, Hammel P, Reni M, et al., Maintenance olaparib for germline BRCA -mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317–327.
   PubMed Web of Science ®Google Scholar
• Fink J. Genomic testing makes inroads after first-line therapy in metastatic pancreatic cancer Targeted Therapies in Oncology. Targeted Therapies in Oncology. 2019;9(16):72.
   Google Scholar
• Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK Fusion–Positive cancers in adults and children. N Engl J Med. 2018;378(8):731–739.
   PubMed Web of Science ®Google Scholar
• Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271–282.
   PubMed Web of Science ®Google Scholar
• Attwood MM, Fabbro D, Sokolov AV, et al. Trends in kinase drug discovery: targets, indications and inhibitor design. Nat Rev Drug Discov. 2021;20(11):839–861.
   PubMed Web of Science ®Google Scholar
• Wilson LJ, Linley A, Hammond DE, et al. New perspectives, opportunities, and challenges in exploring the human protein kinome. Cancer Res. 2018;78(1):15–29.
   PubMed Web of Science ®Google Scholar
• Klaeger S, Heinzlmeir S, Wilhelm M, et al. The target landscape of clinical kinase drugs. Science. 2017;358(6367):6367.
   Web of Science ®Google Scholar
• Pancreatic cancer treatment market size industry report 2018-2025. GVR-1-68038-774-2. San Francisco, CA: Grand View Research; 2017.
   Google Scholar
• Llombart V, Mansour MR. Therapeutic targeting of “undruggable” MYC. Vol. 75. EBioMedicine: Elsevier: 2022.103756
   Google Scholar
• Gunderson AJ, Kaneda MM, Tsujikawa T. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discovery. 2016;6(3):270–285.
   PubMed Web of Science ®Google Scholar
• Jiang H, Hegde S, Knolhoff BL, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22(8):851–860.
   PubMed Web of Science ®Google Scholar
• Biffi G, Oni TE, Spielman B, et al. IL1-Induced JAK/STAT signaling is antagonized by TGFbeta to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 2019;9(2):282–301
   PubMed Web of Science ®Google Scholar
• Principe DR, Timbers KE, Atia LG, et al. TGFbeta signaling in the pancreatic tumor microenvironment. Cancers (Basel). 2021;13(20):5086.
   PubMed Web of Science ®Google Scholar
• Sun X, Gao H, Yang Y, et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019;4:64.
   PubMed Web of Science ®Google Scholar
• Lu H, Zhou Q, He J, et al. Recent advances in the development of protein-protein interactions modulators: mechanisms and clinical trials. Signal Transduct Target Ther. 2020;5(1):213.
   PubMed Web of Science ®Google Scholar
• Zhong L, Li Y, Xiong L, et al. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduct Target Ther. 2021;6(1):201.
   PubMed Web of Science ®Google Scholar
• Rosell R, Aguilar A, Pedraz C, et al. KRAS inhibitors, approved. Nat Cancer. 2021;2(12):1254–1256.
   PubMedGoogle Scholar
• Wang Z, Hausmann S, Lyu R, et al. SETD5-coordinated chromatin reprogramming regulates adaptive resistance to targeted pancreatic cancer therapy. Cancer Cell. 2020;37(6):834–849 e13.
   PubMed Web of Science ®Google Scholar
• Steele NG, Carpenter ES, Kemp SB, et al. Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer. Nat Cancer. 2020;1(11):1097–1112.
   PubMedGoogle Scholar
• Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321(5897):1801–1806.
   PubMed Web of Science ®Google Scholar
• Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52.
   PubMed Web of Science ®Google Scholar
• Ferguson FM, Gray NS. Kinase inhibitors: the road ahead. Nat Rev Drug Discov. 2018;17(5):353–377.
   PubMed Web of Science ®Google Scholar
• Lu Y, Sun H. Progress in the development of small molecular inhibitors of focal adhesion kinase (FAK). J Med Chem. 2020;63(23):14382–14403.
   PubMed Web of Science ®Google Scholar
• Hakim N, Patel R, Devoe C, et al. Why HALO 301 failed and implications for treatment of pancreatic cancer. Pancreas. 2019;3(1):e1–e4.
   PubMedGoogle Scholar
• Neesse A, Frese KK, Bapiro TE, et al. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proc Natl Acad Sci U S A. 2013;110(30):12325–12330.
   PubMed Web of Science ®Google Scholar
• Li D, Schaub N, Guerin TM, et al. T cell-mediated antitumor immunity cooperatively induced By TGFbetaR1 antagonism and gemcitabine counteracts reformation of the stromal barrier in pancreatic cancer. Mol Cancer Ther. 2021;20(10):1926–1940.
   PubMed Web of Science ®Google Scholar
• Zhao Z, Ukidve A, Kim J, et al. Targeting Strategies for Tissue-Specific Drug Delivery. Cell. 2020;181(1):151–167.
   PubMed Web of Science ®Google Scholar
• Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–1461.
   PubMed Web of Science ®Google Scholar
• Kano MR, Bae Y, Iwata C, et al. Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling. Proc Natl Acad Sci U S A. 2007;104(9):3460–3465.
   PubMed Web of Science ®Google Scholar
• Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26(13):2139–2146.
   PubMed Web of Science ®Google Scholar
• Do K, Speranza G, Bishop R, et al. Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer. Invest New Drugs. 2015;33(3):720–728.
   PubMed Web of Science ®Google Scholar
• Bedard PL, Tabernero J, Janku F, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res. 2015;21(4):730–738.
   PubMed Web of Science ®Google Scholar
• Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468(7326):968–972.
   PubMed Web of Science ®Google Scholar
• Mustachio LM, Chelariu-Raicu A, Szekvolgyi L, et al. Targeting KRAS in cancer: promising therapeutic strategies. Cancers (Basel). 2021;13(6):1204.
   PubMed Web of Science ®Google Scholar
• Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest oncology group-directed intergroup trial S0205. J Clin Oncol. 2010;28(22):3605–3610.
   PubMed Web of Science ®Google Scholar
• Safran H, Miner T, Bahary N, et al. Lapatinib and gemcitabine for metastatic pancreatic cancer. A phase II study. Am J Clin Oncol. 2011;34(1):50–52.
   PubMed Web of Science ®Google Scholar
• Wu Z, Gabrielson A, Hwang JJ, et al. Phase II study of lapatinib and capecitabine in second-line treatment for metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2015;76(6):1309–1314.
   PubMed Web of Science ®Google Scholar
• Cohen SJ, O’Neil BH, Berlin J, et al. A phase 1b study of erlotinib in combination with gemcitabine and nab-paclitaxel in patients with previously untreated advanced pancreatic cancer: an Academic Oncology GI Cancer Consortium study. Cancer Chemother Pharmacol. 2016;77(4):693–701.
   PubMed Web of Science ®Google Scholar
• Haas M, Waldschmidt DT, Stahl M, et al. Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: the randomised, open-label phase II ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the ‘burden of therapy’ method. Eur J Cancer. 2021;146:95–106.
   PubMed Web of Science ®Google Scholar
• Cardin DB, Goff L, Li C-I, et al. Phase II trial of sorafenib and erlotinib in advanced pancreatic cancer. Cancer Med. 2014;3(3):572–579.
   PubMed Web of Science ®Google Scholar
• Cohen DJ, Love LL, Ryan E, et al. Phase II study of sorafenib with gemcitabine and erlotinib (GES) in first-line advanced pancreatic cancer. J Clin Oncol. 2011;29(4):266–266.
   Web of Science ®Google Scholar
• Ko AH, Bekaii-Saab T, Van Ziffle J, et al. A multicenter, open-label phase ii clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma. Clin Cancer Res. 2016;22(1):61–68.
   PubMed Web of Science ®Google Scholar
• Halfdanarson TR, Foster NR, Kim GP, et al. A phase ii randomized trial of panitumumab, erlotinib, and gemcitabine versus erlotinib and gemcitabine in patients with untreated, metastatic pancreatic adenocarcinoma: north central cancer treatment group trial N064B (Alliance). Oncologist. 2019;24(5):589–e160.
   PubMed Web of Science ®Google Scholar
• Dent P, Booth L, Roberts JL, et al. Neratinib inhibits hippo/YAP signaling, reduces mutant K-RAS expression, and kills pancreatic and blood cancer cells. Oncogene. 2019;38(30):5890–5904.
   PubMed Web of Science ®Google Scholar
• da Cunha Santos G, Dhani N, Tu D, et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: national cancer institute of Canada clinical trials group study PA.3. Cancer. 2010;116(24):5599–5607.
   PubMed Web of Science ®Google Scholar
• Boeck S, Jung A, Laubender RP, et al. EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer. 2013;108(2):469–476.
   PubMed Web of Science ®Google Scholar
• Boeck S, Jung A, Laubender RP, et al. KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer. J Gastroenterol. 2013;48(4):544–548.
   PubMed Web of Science ®Google Scholar
• Bodoky G, Timcheva C, Spigel DR, et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs. 2012;30(3):1216–1223.
   PubMed Web of Science ®Google Scholar
• Jimeno A, Tan AC, Coffa J, et al. Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer. Cancer Res. 2008;68(8):2841–2849.
   PubMed Web of Science ®Google Scholar
• Infante JR, Somer BG, Park JO, et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur J Cancer. 2014;50(12):2072–2081.
   PubMed Web of Science ®Google Scholar
• Goncalves A, Gilabert M, François E, et al. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 2012;23(11):2799–2805.
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Hidalgo M, Canon J-L, et al. Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. Int J Cancer. 2018;143(8):2053–2064.
   PubMed Web of Science ®Google Scholar
• Chung V, McDonough S, Philip PA, et al., Effect of Selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol. 2017;3(4):516–522.
   PubMed Web of Science ®Google Scholar
• Tolcher AW, Bendell JC, Papadopoulos KP, et al. A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors. Ann Oncol. 2015;26(1):58–64.
   PubMed Web of Science ®Google Scholar
• LoRusso P, De Vos FYFL FM, Beck JT, et al. Phase Ib study of ribociclib (R) + trametinib (T) in patients (pts) with metastatic/advanced solid tumours. Ann Oncol. 2020;31:S484.
   Google Scholar
• Van Laethem JL, Riess H, Jassem J, et al. Phase I/II study of refametinib (BAY 86-9766) in combination with gemcitabine in advanced pancreatic cancer. Target Oncol. 2017;12(1):97–109.
   PubMed Web of Science ®Google Scholar
• Kenney C, Kunst T, Webb S, et al. Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRAS(G12R)-mutant pancreatic ductal adenocarcinoma. Invest New Drugs. 2021;39(3):821–828.
   PubMed Web of Science ®Google Scholar
• Bryant KL, Stalnecker CA, Zeitouni D, et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med. 2019;25(4):628–640.
   PubMed Web of Science ®Google Scholar
• Hobbs GA, Baker NM, Miermont AM, et al. Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. Cancer Discov. 2020;10(1):104–123.
   PubMed Web of Science ®Google Scholar
• Franco J, Witkiewicz AK, Knudsen ES. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget. 2014;5(15):6512–6525.
   PubMed Web of Science ®Google Scholar
• Franco J, Balaji U, Freinkman E, et al. Metabolic reprogramming of pancreatic cancer mediated by CDK4/6 inhibition elicits unique vulnerabilities. Cell Rep. 2016;14(5):979–990.
   PubMed Web of Science ®Google Scholar
• Poulikakos PI, Solit DB. Resistance to MEK inhibitors: should we co-target upstream? Sci Signal. 2011;4(166):e16.
   Web of Science ®Google Scholar
• Fedele C, Ran H, Diskin B, et al., SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models. Cancer Discov. 2018;8(10): 1237–1249.
   PubMed Web of Science ®Google Scholar
• Ruess DA, Heynen GJ, Ciecielski KJ, et al. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat Med. 2018;24(7):954–960.
   PubMed Web of Science ®Google Scholar
• Ahmed TA, Adamopoulos C, Karoulia Z, et al. SHP2 drives adaptive resistance to ERK signaling inhibition in molecularly defined subsets of ERK-dependent tumors. Cell Rep. 2019;26(1):65–78 e5.
   PubMed Web of Science ®Google Scholar
• Ryan MB, Fece de la Cruz F, Phat S, et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS(G12C) Inhibition. Clin Cancer Res. 2020;26(7):1633–1643.
   PubMed Web of Science ®Google Scholar
• Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–223.
   PubMed Web of Science ®Google Scholar
• Fedele C, Li S, Teng KW, et al. SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J Exp Med. 2021;218(1). 10.1084/jem.20201414.
   PubMed Web of Science ®Google Scholar
• Witkiewicz AK, McMillan EA, Balaji U, et al., Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015;6(1): 6744.
   PubMedGoogle Scholar
• Ying H, Elpek KG, Vinjamoori A, et al. PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-kappaB-cytokine network. Cancer Discov. 2011;1(2):158–169.
   PubMed Web of Science ®Google Scholar
• McRee AJ, Sanoff HK, Carlson C, et al. A phase I trial of mFOLFOX6 combined with the oral PI3K inhibitor BKM120 in patients with advanced refractory solid tumors. Invest New Drugs. 2015;33(6):1225–1231.
   PubMed Web of Science ®Google Scholar
• O’Neil BH, Scott AJ, Ma WW, et al. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. Ann Oncol. 2015;26(12):2505.
   PubMed Web of Science ®Google Scholar
• Richards DA, Kuefler PR, Becerra C, et al. Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: results of a phase II, randomized, noncomparative study. Invest New Drugs. 2011;29(1):144–153.
   PubMed Web of Science ®Google Scholar
• Naing A, Powderly JD, Nemunaitis JJ, et al. Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with epacadostat or parsaclisib in advanced solid tumors: a phase I study. J Immunother Cancer. 2022;10(3):e004223.
   PubMed Web of Science ®Google Scholar
• Wolpin BM, Hezel AF, Abrams T, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2009;27(2):193–198.
   PubMed Web of Science ®Google Scholar
• Kordes S, Richel DJ, Klümpen H-J, et al. A phase I/II, non-randomized, feasibility/safety and efficacy study of the combination of everolimus, cetuximab and capecitabine in patients with advanced pancreatic cancer. Invest New Drugs. 2013;31(1):85–91.
   PubMed Web of Science ®Google Scholar
• Karavasilis V, Samantas E, Koliou G-A, et al. Gemcitabine combined with the mTOR inhibitor temsirolimus in patients with locally advanced or metastatic pancreatic cancer. A hellenic cooperative oncology group phase I/II study. Target Oncol. 2018;13(6):715–724.
   PubMed Web of Science ®Google Scholar
• Conway JR, Herrmann D, Evans TJ, et al. Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine. Gut. 2019;68(4):742–758.
   PubMed Web of Science ®Google Scholar
• Andre F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA -Mutated, Hormone Receptor–Positive Advanced Breast Cancer. N Engl J Med. 2019;380(20):1929–1940.
   PubMed Web of Science ®Google Scholar
• Hu C, Dadon T, Chenna V, et al. Combined inhibition of cyclin-dependent kinases (Dinaciclib) and AKT (MK-2206) blocks pancreatic tumor growth and metastases in patient-derived xenograft models. Mol Cancer Ther. 2015;14(7):1532–1539.
   PubMed Web of Science ®Google Scholar
• Hochwald SN, Nyberg C, Zheng M, et al. A novel small molecule inhibitor of FAK decreases growth of human pancreatic cancer. Cell Cycle. 2009;8(15):2435–2443.
   PubMed Web of Science ®Google Scholar
• Murphy JM, Rodriguez YAR, Jeong K, et al. Targeting focal adhesion kinase in cancer cells and the tumor microenvironment. Exp Mol Med. 2020;52(6):877–886.
   PubMed Web of Science ®Google Scholar
• Aung KL, Welch ME, Wang S, et al. A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma (PDAC) (MOBILITY-002 Trial, NCT02428270). J Clin Oncol. 2018;36(4):409–409.
   Web of Science ®Google Scholar
• Wang-Gillam A, Lockhart MR, Tan AC, et al. Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer: experiences of pancreatic ductal adenocarcinoma (PDAC) patients. Cancer Res. 2020;80(16_Supplement):CT118–CT118. abstract CT118.
   Google Scholar
• Evans TRJ, Van Cutsem E, Moore MJ, et al. Phase 2 placebo-controlled, double-blind trial of dasatinib added to gemcitabine for patients with locally-advanced pancreatic cancer. Ann Oncol. 2017;28(2):354–361.
   PubMed Web of Science ®Google Scholar
• Chee CE, Krishnamurthi S, Nock CJ, et al. Phase II study of dasatinib (BMS-354825) in patients with metastatic adenocarcinoma of the pancreas. Oncologist. 2013;18(10):1091–1092.
   PubMed Web of Science ®Google Scholar
• George TJ, Ali A, Wang Y, et al. Phase II study of 5-fluorouracil, oxaliplatin plus dasatinib (FOLFOX-D) in first-line metastatic pancreatic adenocarcinoma. Oncologist. 2021;26(10):825–e1674.
   PubMed Web of Science ®Google Scholar
• Messersmith WA, Arcaroli NS, Tan J, et al. A phase II trial of saracatinib (AZD0530), an oral Src inhibitor, in previously treated metastatic pancreatic cancer. J Clin Oncol. 2010;28(15):e14515–e14515.
   Web of Science ®Google Scholar
• Renouf DJ, Moore MJ, Hedley D, et al. A phase I/II study of the Src inhibitor saracatinib (AZD0530) in combination with gemcitabine in advanced pancreatic cancer. Invest New Drugs. 2012;30(2):779–786.
   PubMed Web of Science ®Google Scholar
• Subbiah V, Iannotti NO, Gutierrez M, et al., FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies. Ann Oncol. 2022;33(5): 522–533.
   PubMed Web of Science ®Google Scholar
• Lenkiewicz E, Malasi S, Hogenson TL, et al. Genomic and epigenomic landscaping defines new therapeutic targets for adenosquamous carcinoma of the pancreas. Cancer Res. 2020;80(20):4324–4334.
   PubMed Web of Science ®Google Scholar
• Thomas D, Radhakrishnan P. Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis. Mol Cancer. 2019;18(1):14.
   PubMedGoogle Scholar
• Pothula SP, Xu Z, Goldstein D, et al. Targeting HGF/c-MET Axis in Pancreatic Cancer. Int J Mol Sci. 2020;21(23):9170.
   Web of Science ®Google Scholar
• Hage C, Rausch V, Giese N, et al. The novel c-Met inhibitor cabozantinib overcomes gemcitabine resistance and stem cell signaling in pancreatic cancer. Vol. 4. London, UK: Cell Death Dis; 2013. p. e627.
   Google Scholar
• Li C, Wu J, Hynes M, et al. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology. 2011;141(6):2218–2227 e5.
   PubMed Web of Science ®Google Scholar
• Zhen DB, Griffith KA, Ruch JM, et al. A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer. Invest New Drugs. 2016;34(6):733–739.
   PubMed Web of Science ®Google Scholar
• Du W, Brekken RA. Does Axl have potential as a therapeutic target in pancreatic cancer? Expert Opin Ther Targets. 2018;22(11):955–966.
   PubMed Web of Science ®Google Scholar
• Bellomo G, Rainer C, Quaranta V, et al. Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. Gut. 2022;8:228–229.
   Google Scholar
• Perkhofer L, Gout J, Roger E, et al. DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives. Gut. 2021;70(3):606–617.
   PubMed Web of Science ®Google Scholar
• Crowley F, Park W, O’Reilly EM. Targeting DNA damage repair pathways in pancreas cancer. Cancer Metastasis Rev. 2021;40(3):891–908.
   PubMed Web of Science ®Google Scholar
• Javle M, Shacham-Shmueli E, Xiao L, et al., Olaparib monotherapy for previously treated pancreatic cancer with DNA damage repair genetic alterations other than germline BRCA variants. JAMA Oncol. 2021;7(5): 693–699.
   PubMed Web of Science ®Google Scholar
• Bian Y, Teper Y, Mathews Griner LA, et al. Target deconvolution of a multikinase inhibitor with antimetastatic properties identifies TAOK3 as a key contributor to a cancer stem cell-like phenotype. Mol Cancer Ther. 2019;18(11):2097–2110.
   PubMed Web of Science ®Google Scholar
• Vitale I, Manic G, De Maria R, et al. DNA Damage in Stem Cells. Mol Cell. 2017;66(3):306–319.
   PubMed Web of Science ®Google Scholar
• Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell. 2015;16(3):225–238.
   PubMed Web of Science ®Google Scholar
• Laquente B, Lopez-Martin J, Richards D, et al. A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients. BMC Cancer. 2017;17(1):137.
   PubMed Web of Science ®Google Scholar
• Mross K, Dittrich C, Aulitzky WE, et al. A randomised phase II trial of the Polo-like kinase inhibitor BI 2536 in chemo-naive patients with unresectable exocrine adenocarcinoma of the pancreas - a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network. Br J Cancer. 2012;107(2):280–286.
   PubMed Web of Science ®Google Scholar
• Thomas A, Redon CE, Sciuto L, et al. Phase I study of ATR inhibitor M6620 in combination with topotecan in patients with advanced solid tumors. J Clin Oncol. 2018;36(16):1594–1602.
   PubMed Web of Science ®Google Scholar
• Thomas A, Takahashi N, Rajapakse VN, et al. Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress. Cancer Cell. 2021;39(4):566–579 e7.
   PubMed Web of Science ®Google Scholar
• Ghelli Luserna Di Rora A, Cerchione C, Martinelli G, et al. A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target. J Hematol Oncol. 2020;13(1):126.
   PubMed Web of Science ®Google Scholar
• O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13(7):417–430.
   PubMed Web of Science ®Google Scholar
• Carvajal RD, Tse A, Shah MA, et al. A phase II study of flavopiridol (Alvocidib) in combination with docetaxel in refractory, metastatic pancreatic cancer. Pancreatology. 2009;9(4):404–409.
   PubMed Web of Science ®Google Scholar
• Gansauge S, Gansauge F, Ramadani M, et al. Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res. 1997;57(9):1634–1637.
   PubMed Web of Science ®Google Scholar
• Kornmann M, Arber N, Korc M. Inhibition of basal and mitogen-stimulated pancreatic cancer cell growth by cyclin D1 antisense is associated with loss of tumorigenicity and potentiation of cytotoxicity to cisplatinum. J Clin Invest. 1998;101(2):344–352.
   PubMed Web of Science ®Google Scholar
• Salvador-Barbero B, Alvarez-Fernández M, Zapatero-Solana E, et al. CDK4/6 inhibitors impair recovery from cytotoxic chemotherapy in pancreatic adenocarcinoma. Cancer Cell. 2020;38(4):584.
   PubMed Web of Science ®Google Scholar
• Al Baghdadi T, Halabi S, Garrett-Mayer E, et al. Palbociclib in Patients With Pancreatic and Biliary Cancer With CDKN2A Alterations: results From the Targeted Agent and Profiling Utilization Registry Study. JCO Precis Oncol. 2019;3:1–8.
   PubMedGoogle Scholar
• Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25–35.
   PubMed Web of Science ®Google Scholar
• Andre F, Campone SS, Petrakova M, et al. Ribociclib + letrozole for first-line treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): efficacy by baseline tumor markers. Cancer Res. 2017;77(13):CT045–CT045.
   Google Scholar
• Murphy AG, Zahurak M, Shah M, et al. A phase i study of dinaciclib in combination with MK-2206 in patients with advanced pancreatic cancer. Clin Transl Sci. 2020;13(6):1178–1188.
   PubMed Web of Science ®Google Scholar
• Suski JM, Ratnayeke N, Braun M, et al. CDC7-independent G1/S transition revealed by targeted protein degradation. Nature. 2022;605(7909):357–365.
   PubMed Web of Science ®Google Scholar
• Nagathihalli NS, Castellanos JA, Shi C, et al. Signal transducer and activator of transcription 3, mediated remodeling of the tumor microenvironment results in enhanced tumor drug delivery in a mouse model of pancreatic cancer. Gastroenterology. 2015;149(7):1932–1943 e9.
   PubMed Web of Science ®Google Scholar
• Denley SM, Jamieson NB, McCall P, et al. Activation of the IL-6R/Jak/stat pathway is associated with a poor outcome in resected pancreatic ductal adenocarcinoma. J Gastrointest Surg. 2013;17(5):887–898.
   PubMed Web of Science ®Google Scholar
• White CM, Martin BK, Lee L-F, et al. Effects of paclitaxel on cytokine synthesis by unprimed human monocytes, T lymphocytes, and breast cancer cells. Cancer Immunol Immunother. 1998;46(2):104–112.
   PubMed Web of Science ®Google Scholar
• Rajput S, Volk-Draper LD, Ran S. TLR4 is a novel determinant of the response to paclitaxel in breast cancer. Mol Cancer Ther. 2013;12(8):1676–1687.
   PubMed Web of Science ®Google Scholar
• Karakasheva TA, Lin EW, Tang Q, et al. IL-6 mediates cross-talk between tumor cells and activated fibroblasts in the tumor microenvironment. Cancer Res. 2018;78(17):4957–4970.
   PubMed Web of Science ®Google Scholar
• Sheridan C. Pancreatic cancer provides testbed for first mechanotherapeutics. Nat Biotechnol. 2019;37(8):829–831.
   PubMed Web of Science ®Google Scholar
• Hurwitz H, Van Cutsem E, Bendell J, et al. Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies. Invest New Drugs. 2018;36(4):683–695.
   PubMed Web of Science ®Google Scholar
• Beatty GL, Shahda S, Beck T, et al. A phase Ib/II study of the JAK1 Inhibitor, Itacitinib, plus nab -paclitaxel and gemcitabine in advanced solid tumors. Oncologist. 2019;24(1):14–e10.
   PubMed Web of Science ®Google Scholar
• Principe DR, DeCant B, Mascariñas E, et al. TGFbeta signaling in the pancreatic tumor microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis. Cancer Res. 2016;76(9):2525–2539.
   PubMed Web of Science ®Google Scholar
• Melisi D, Garcia-Carbonero R, Macarulla T, et al. Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer. Br J Cancer. 2018;119(10):1208–1214.
   PubMed Web of Science ®Google Scholar
• Melisi D, Oh D-Y, Hollebecque A, et al. Safety and activity of the TGFbeta receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer. J Immunother Cancer. 2021;9(3):e002068.
   PubMed Web of Science ®Google Scholar
• Chen Z, Zhang N, Chu HY, et al. Connective tissue growth factor: from molecular understandings to drug discovery. Front Cell Dev Biol. 2020;8:593269.
   PubMed Web of Science ®Google Scholar
• Mpekris F, Voutouri C, Baish JW, et al. Combining microenvironment normalization strategies to improve cancer immunotherapy. Proc Natl Acad Sci U S A. 2020;117(7):3728–3737.
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Vervenne WL, Bennouna J, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27(13):2231–2237.
   PubMed Web of Science ®Google Scholar
• Tong RT, Boucher Y, Kozin SV, et al. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004;64(11):3731–3736.
   PubMed Web of Science ®Google Scholar
• Sitohy B, Nagy JA, Dvorak HF. Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res. 2012;72(8):1909–1914.
   PubMed Web of Science ®Google Scholar
• Kindler HL, Ioka T, Richel DJ, et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011;12(3):256–262.
   PubMed Web of Science ®Google Scholar
• Dragovich T, Laheru D, Dayyani F, et al. Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001). Cancer Chemother Pharmacol. 2014;74(2):379–387.
   PubMed Web of Science ®Google Scholar
• Middleton G, Palmer DH, Greenhalf W, et al. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017;18(4):486–499.
   PubMed Web of Science ®Google Scholar
• Ma WW, Xie H, Fetterly G, et al. A Phase Ib Study of the FGFR/VEGFR inhibitor dovitinib with gemcitabine and capecitabine in advanced solid tumor and pancreatic cancer patients. Am J Clin Oncol. 2019;42(2):184–189.
   PubMed Web of Science ®Google Scholar
• Wu H, Zhao C HN. Outcomes of anlotinib plus nab-paclitaxel/gemcitabine as first-line treatment for patients with advanced pancreatic adenocarcinoma: a retrospective analysis in China. J Clin Oncol. 2022;40(4):772–783.
   PubMed Web of Science ®Google Scholar
• Bozzarelli S, Rimassa L, Giordano L, et al. Regorafenib in patients with refractory metastatic pancreatic cancer: a Phase II study (RESOUND). Future Oncol. 2019;15(35):4009–4017.
   PubMed Web of Science ®Google Scholar
• Aoto K, Ito K, Aoki S. Complex formation between platelet-derived growth factor receptor beta and transforming growth factor beta receptor regulates the differentiation of mesenchymal stem cells into cancer-associated fibroblasts. Oncotarget. 2018;9(75):34090–34102.
   PubMedGoogle Scholar
• Li T, Guo T, Liu H, et al. Plateletderived growth factorBB mediates pancreatic cancer malignancy via regulation of the Hippo/Yesassociated protein signaling pathway. Oncol Rep. 2021;45(1):83–94.
   PubMed Web of Science ®Google Scholar
• Deplanque G, Demarchi M, Hebbar M, et al. A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer. Ann Oncol. 2015;26(6):1194–1200.
   PubMed Web of Science ®Google Scholar
• Ezenfis JHO, Hermine O. Masitinib plus gemcitabine as first-line treatment of pancreatic cancer with pain: results from phase 3 study AB12005. J Clin Oncol. 2021;39(15):4018–4018.
   Web of Science ®Google Scholar
• Tempero M, Oh D-Y, Tabernero J, et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study. Ann Oncol. 2021;32(5):600–608.
   PubMed Web of Science ®Google Scholar
• Hong D, Rasco D, Veeder M, et al. A phase 1b/2 Study of the bruton tyrosine kinase inhibitor ibrutinib and the PD-L1 inhibitor durvalumab in patients with pretreated solid tumors. Oncology. 2019;97(2):102–111.
   PubMed Web of Science ®Google Scholar
• O’Hara MH, Wolff RA ORE, O’Hara MH. Gemcitabine (Gem) and nab-paclitaxel (NP) ± nivolumab (nivo) ± CD40 agonistic monoclonal antibody APX005M (sotigalimab), in patients (Pts) with untreated metastatic pancreatic adenocarcinoma (mPDAC): phase (Ph) 2 final results. J Clin Oncol. 2021;39(15):2497–2505.
   PubMed Web of Science ®Google Scholar
• Le DT, Wang-Gillam A, Picozzi V, et al. Safety and Survival With GVAX pancreas prime and listeria Monocytogenes –expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015;33(12):1325–1333.
   PubMed Web of Science ®Google Scholar
• Singhi AD, Ali SM, Lacy J, et al. Identification of targetable ALK rearrangements in pancreatic ductal adenocarcinoma. J Natl Compr Canc Netw. 2017;15(5):555–562.
   PubMed Web of Science ®Google Scholar
• Subbiah V, Bauer T KB, Bauer T. Abstract CT011: efficacy and safety of selpercatinib in RET fusion-positive cancers other than lung or thyroid cancers. Cancer Res. 2021;81(13):CT011–CT011.
   Web of Science ®Google Scholar