Clinical development landscape in GIST: from novel agents that target accessory pathways to revisiting non-targeted therapies

References

• Nilsson B, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era–a population-based study in western Sweden. Cancer. 2005;103:821–829.
   PubMed Web of Science ®Google Scholar
• Demetri GD, Von Mehren M, Antonescu CR, et al. NCCN task force report: management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw. 2010;8:S1–42.
   PubMed Web of Science ®Google Scholar
• Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–580.
   PubMed Web of Science ®Google Scholar
• Nakahara M, Isozaki K, Hirota S, et al. A novel gain-of-function mutation of c-KIT gene in gastrointestinal stromal tumor. Gastroenterol. 1998;115:1090–1095.
   PubMed Web of Science ®Google Scholar
• Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708–710.
   PubMed Web of Science ®Google Scholar
• ESMO/European Sarcoma Network Working Group. Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25:iii21–6.
   PubMed Web of Science ®Google Scholar
• NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Soft Tissue Sarcoma. V.2.2016. Fort Worth, PA: National Comprehensive Cancer Network Inc, 2016.  [cited 2016 Nov 30].
   Google Scholar
• DeMatteo RP, Heinrich MC, El-Rifai WM, et al. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol. 2002;33:466–477.
   PubMed Web of Science ®Google Scholar
• Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26:626–632.
   PubMed Web of Science ®Google Scholar
• Von Mehren M, Heinrich MC, Joensuu H, et al. Follow-up results after 9 years of the ongoing phase II B2222 trial of imatinib mesylate in patients with metastatic or unresectable KIT+ gastrointestinal stromal tumors (GIST). J Clin Oncol. 2011;29:[abstract 10016].
   PubMed Web of Science ®Google Scholar
• Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364:1127–1134.
   PubMed Web of Science ®Google Scholar
• Blanke CD, Demetri GD, Von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620–625.
   PubMed Web of Science ®Google Scholar
• Stivarga (regorafenib) [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc; August 2016.
   Google Scholar
• Sutent (sunitinib) [package insert]. New York, NY: Pfizer Pharmaceuticals; April 2015.
   Google Scholar
• Kang YK, Ryu MH, Yoo C, et al. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013;14:1175–1182.
   PubMed Web of Science ®Google Scholar
• Heinrich MC, Maki RG, Corless CL, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008;26:5352–5359.
   PubMed Web of Science ®Google Scholar
• Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342–4349.
   PubMed Web of Science ®Google Scholar
• Debiec-Rychter M, Cools J, Dumez H, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology. 2005;128:270–279.
   PubMed Web of Science ®Google Scholar
• Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24:4764–4774.
   PubMed Web of Science ®Google Scholar
• Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005;23:5357–5364.
   PubMed Web of Science ®Google Scholar
• Sleijfer S, Wiemer E, Seynaeve C, et al. Improved insight into resistance mechanisms to imatinib in gastrointestinal stromal tumors: a basis for novel approaches and individualization of treatment. The Oncologist. 2007;12:719–726.
   PubMed Web of Science ®Google Scholar
• Miranda C, Nucifora M, Molinari F, et al. KRAS and BRAF mutations predict primary resistance to imatinib in gastrointestinal stromal tumors. Clin Cancer Res. 2012;18:1769–1776.
   PubMed Web of Science ®Google Scholar
• Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 2006;42:1093–1103.
   PubMed Web of Science ®Google Scholar
• Heinrich MC, Owzar K, Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008;26:5360–5367.
   PubMed Web of Science ®Google Scholar
• Janeway KA, Liegl B, Harlow A, et al. Pediatric KIT–wild-type and platelet-derived growth factor receptor a–wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors. Cancer Res. 2007;67:9084–9088.
   PubMed Web of Science ®Google Scholar
• Sankhala KK, Papadopoulos KP. Future options for imatinib mesylate-resistant tumors. Expert Opin Investig Drugs. 2007;16:1549–1560.
   PubMed Web of Science ®Google Scholar
• Reichardt P, Reichardt A, Pink D. Molecular targeted therapy of gastrointestinal stromal tumors. Curr Cancer Drug Targets. 2011;11:688–697.
   PubMed Web of Science ®Google Scholar
• Demetri GD. Differential properties of current tyrosine kinase inhibitors in gastrointestinal stromal tumors. Semin Oncol. 2011;38:S10–19.
   PubMed Web of Science ®Google Scholar
• Serrano C, George S. Recent advances in the treatment of gastrointestinal stromal tumors. Ther Adv Med Oncol. 2014;6:115–127.
   PubMed Web of Science ®Google Scholar
• Mahadevan D, Cooke L, Riley C, et al. A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene. 2007;26:3909–3919.
   PubMed Web of Science ®Google Scholar
• Regad T. Targeting RTK signaling pathways in cancers. Cancers (Basel). 2015;7:1758–1784.
   PubMed Web of Science ®Google Scholar
• Mahadevan D, Theiss N, Morales C, et al. Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST). Oncotarget. 2015;6:1954–1966.
   PubMed Web of Science ®Google Scholar
• Janku F, George S, Razak A, et al. DCC-2618, a pan KIT and PDGFR switch control inhibitor, achieves proof-of-concept in a first-in-human study. Eur J Cancer. 2016;68:[abstract LBA7].
   Google Scholar
• Heinrich M, Jones R, Schoffski P, et al. Preliminary safety and activity in a first-in-human phase 1 study of BLU-285, a potent, highly-selective inhibitor of KIT and PDGFRα activation loop mutants in advanced gastrointestinal stromal tumor (GIST). Eur J Cancer. 2016;68:[abstract LBA6].
   Google Scholar
• Matro JM, Yu JQ, Heinrich MC, et al. Correlation of PET/CT and CT RECIST response in GIST patients with PDGFRA D842V gene mutations treated with crenolanib. J Clin Oncol. 2014;32:[abstract 10546].
   Web of Science ®Google Scholar
• Nokihara H, Yamamoto N, Nakamichi S, et al. Phase 1 study of cabozantinib in Japanese patients with advanced solid tumors: anti-tumor activity in NSCLC and GIST. Ann Oncol. 2013;24:[abstract O2–026].
   Web of Science ®Google Scholar
• Zhou A, Zhang W, Chang C, et al. Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib. Cancer Chemother Pharmacol. 2013;72:1043–1053.
   PubMed Web of Science ®Google Scholar
• LeCesne A, Blay J, Bui BN, et al. Phase II study of oral masitinib mesilate in imatinib-naive patients with locally advanced or metastatic gastrointestinal stromal tumors (GIST). Eur J Cancer. 2010;46:1344–1351.
   PubMed Web of Science ®Google Scholar
• Blay J, Le Cesne A, Bin Bui N, et al. Overall survival benefit with masitinib mesylate in imatinib-naive, locally advanced, or metastatic gastrointestinal stromal tumor (GIST): 4-years follow-up of the French Sarcoma Group phase II trial. J Clin Oncol. 2011;29:[abstract 85].
   PubMed Web of Science ®Google Scholar
• Adenis A, Blay JY, Bui-Nguyen B, et al. Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: a randomized controlled open-label trial. Ann Oncol. 2014;25:1762–1769.
   PubMed Web of Science ®Google Scholar
• Yap TA, Arkenau HT, Camidge DR, et al. First-in-human phase I trial of two schedules of OSI-930, a novel multikinase inhibitor, incorporating translational proof-of-mechanism studies. Clin Cancer Res. 2013;19:909–919.
   PubMed Web of Science ®Google Scholar
• Ganjoo KN, Villalobos VM, Kamaya A, et al. A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib. Ann Oncol. 2014;25:236–240.
   PubMed Web of Science ®Google Scholar
• Blay J, Molimard M, Cropet C, et al. Final results of the multicenter randomized phase II PAZOGIST trial evaluating the efficacy of pazopanib (P) plus best supportive care (BSC) vs BSC alone in resistant unresectable metastatic and/or locally advanced gastrointestinal stromal tumors (GIST). J Clin Oncol. 2015;33:[abstract 10506].
   Google Scholar
• Eriksson M, Reichard P, Joensuu H, et al. Pazopanib as third line treatment in advanced GIST progressive after treatment with imatinib and sunitinib - results from a phase II trial (SSG XXI, PAGIST). GIST Cancer J. 2015;2(4) [abstract P060].
   Google Scholar
• Heinrich CM, Von Mehren M, Demetri GD, et al. Ponatinib efficacy and safety in patients (pts) with advanced gastrointestinal stromal tumors (GIST) after tyrosine kinase inhibitor (TIK) failure: results from a phase 2 study. J Clin Oncol. 2015;33:[abstract 10535].
   Web of Science ®Google Scholar
• Kang Y, Yoo C, Ryoo B, et al. Phase II study of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib. Br J Cancer. 2013;109:2309–2315.
   PubMed Web of Science ®Google Scholar
• Schöffski P, Reichardt P, Blay J, et al. A phase I–II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors. Ann Oncol. 2010;21:1990–1998.
   PubMed Web of Science ®Google Scholar
• Hohenberger P, Bauer S, Gruenwald V, et al. Multicenter, single-arm, two-state phase II trial of everolimus (RAD001) with imatinib in imatinib-resistant patients (pts) with advanced GIST. J Clin Oncol. 2010;28:[abstract 10048].
   Web of Science ®Google Scholar
• Conley AP, Araujo D, Ludwig J, et al. A randomized phase II study of perifosine (P) plus imatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST). J Clin Oncol. 2009;37:[abstract 10563].
   Google Scholar
• Chi P, Qin L, D’Angelo SP, et al. A phase Ib/II study of MEK162 (binimetinib [BIN]) in combination with imatinib in patients with advanced gastrointestinal stromal tumors (GIST). J Clin Oncol. 2015;33:[abstract 10507].
   Web of Science ®Google Scholar
• Shapiro GI, Kwak E, Dezube BJ, et al. First-in-human phase I dose escalation study of a second-generation non-ansamycin HSP90 inhibitor, AT13387, in patients with advanced solid tumors. Clin Cancer Res. 2015;21:87–97.
   PubMed Web of Science ®Google Scholar
• Chiang N, Yeh K, Chiu F, et al. Results of a phase II trial of AUY922, a novel heat shock protein inhibitor in patients with metastatic gastrointestinal stromal tumor (GIST) and imatinib band sunitinib therapy. J Clin Oncol. 2016;34:[abstract 134].
   Web of Science ®Google Scholar
• Blanke CD, Rankin C, Corless C, et al. S0502: a SWOG phase III randomized study of imatinib, with or without bevacizumab, in patients with untreated metastatic or unresectable gastrointestinal stromal tumors. Oncologist. 2015;20:1353–1354.
   PubMed Web of Science ®Google Scholar
• D’Angelo SP, Shoushtari AN, Keohan ML, et al. Combined KIT and CTLA-4 blockade in patients with refractory GIST and other advanced sarcomas: phase 1b study of dasatinib plus ipilimumab (NCI #9172). GIST Cancer J. 2015;2(4) [abstract P052].
   Google Scholar
• US National Institutes of Health. ClinicalTrials.gov. [ cited 2016 Nov 15]. Available at www.clinicaltrials.gov
   Google Scholar
• Li J, Dang Y, Gao J, et al. PI3K/AKT/mTOR pathway is activated after imatinib secondary resistance in gastrointestinal stromal tumors (GISTs). Med Oncol. 2015;32:111.
   PubMed Web of Science ®Google Scholar
• Patel S. Exploring novel therapeutic targets in GIST: focus on the PI3K/Akt/mTOR pathway. Curr Oncol Rep. 2013;15:386–395.
   PubMed Web of Science ®Google Scholar
• Agaram NP, Wong GC, Guo T, et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2008;47:853–859.
   PubMed Web of Science ®Google Scholar
• Mahalingam D, Swords R, Carew JS, et al. Targeting HSP90 for cancer therapy. Br J Cancer. 2009;100:1523–1529.
   PubMed Web of Science ®Google Scholar
• Conforti F, Wang Y, Rodriguez JA, et al. Molecular pathways: anticancer activity by inhibition of nucleocytoplasmic shuttling. Clin Cancer Res. 2015;21:4508–4513.
   PubMed Web of Science ®Google Scholar
• Saponara M, Urbini M, Astolfi A, et al. Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRalpha genotype evaluated by next generation sequencing (NGS). Oncotarget. 2015;6:42243–42257.
   PubMed Web of Science ®Google Scholar
• Xu Z, Huo X, Tang C, et al. Frequent KIT mutations in human gastrointestinal stromal tumors. Sci Rep. 2014;4:5907.
   PubMed Web of Science ®Google Scholar
• Schoppmann SF, Vinatzer U, Popitsch N, et al. Novel clinically relevant genes in gastrointestinal stromal tumors identified by exome sequencing. Clin Cancer Res. 2013;19:5329–5339.
   PubMed Web of Science ®Google Scholar
• Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012;12:278–287.
   PubMed Web of Science ®Google Scholar
• Plaat BEC, Hollema H, Molenaar WM, et al. Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins. J Clin Oncol. 2000;18:3211–3220.
   PubMed Web of Science ®Google Scholar
• Blay JY, Casali PG, Dei Tos AP, et al. Management of gastrointestinal stromal tumour: current practices and visions for the future. Oncology. 2015;89:1–13.
   PubMed Web of Science ®Google Scholar
• Pessetto ZY, Ma Y, Hirst JJ, et al. Drug repurposing identifies a synergistic combination therapy with imatinib mesylate for gastrointestinal stromal tumor. Mol Cancer Ther. 2014;13:2276–2287.
   PubMed Web of Science ®Google Scholar
• Boichuk S, Lee DJ, Mehalek KR, et al. Unbiased compound screening identifies unexpected drug sensitivities and novel treatment options for gastrointestinal stromal tumors. Cancer Res. 2014;74:1200–1213.
   PubMed Web of Science ®Google Scholar
• DeNardo DG, Brennan DJ, Rexhepaj E, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011;1:54–67.
   PubMed Web of Science ®Google Scholar
• Kim TS, Cavnar MJ, Cohen NA, et al. Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor. Clin Cancer Res. 2014;20:2350–2362.
   PubMed Web of Science ®Google Scholar
• Bollag G. Optimizing kinase inhibitors to treat cancer. Cancer Res. 2016;76:[abstract IA32].
   Web of Science ®Google Scholar
• Smith BD, Hood MM, Wise SC, et al. DCC-2618 is a potent inhibitor of wild-type and mutant KIT, including refractory exon 17 D816 KIT mutations, and exhibits efficacy in refractory GIST and AML xenograft models. Cancer Res. 2015;75:[abstract 2690].
   Web of Science ®Google Scholar
• Heinrich MC, Griffith D, McKinley A, et al. Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. Clin Cancer Res. 2012;18:4375–4384.
   PubMed Web of Science ®Google Scholar
• Evans EK, Hodous BL, Gardino AK, et al. BLU-285, the first selective inhibitor of PDGFRa D842V and KIT Exon 17 mutants. Cancer Res. 2015;75:[abstract 791].
   Web of Science ®Google Scholar
• Javidi-Sharifi N, Traer E, Martinez J, et al. Crosstalk between KIT and FGFR3 promotes gastrointestinal stromal tumor cell growth and drug resistance. Cancer Res. 2015;75:880–891.
   PubMed Web of Science ®Google Scholar
• Guagnano V, Furet P, Spanka C, et al. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamin o]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem. 2011;54:7066–7083.
   PubMed Web of Science ®Google Scholar
• Lee SH, Lopes De Menezes D, Vora J, et al. In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models. Clin Cancer Res. 2005;11:3633–3641.
   PubMed Web of Science ®Google Scholar
• Sarker D, Molife R, Evans TRJ, et al. A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin Cancer Res. 2008;14:2075–2081.
   PubMed Web of Science ®Google Scholar
• Yoo C, Ryu MH, Na YS, et al. Analysis of serum protein biomarkers, circulating tumor DNA, and dovitinib activity in patients with tyrosine kinase inhibitor-refractory gastrointestinal stromal tumors. Ann Oncol. 2014;25:2272–2277.
   PubMed Web of Science ®Google Scholar
• Gebreyohannes YK, Van Looy T, Wozniak A, et al. Anti-tumor effects of dovitinib, a multi-target kinase inhibitor, in patient-derived gastrointestinal stromal tumor (GIST) xenograft models. Cancer Res. 2015;75:[abstract 775].
   Web of Science ®Google Scholar
• Smith NR, Baker D, James NH, et al. Vascular endothelial growth factor receptors VEGFR-2 and VEGFR-3 are localized primarily to the vasculature in human primary solid cancers. Clin Cancer Res. 2010;16:3548–3561.
   PubMed Web of Science ®Google Scholar
• Dubreuil P, Letard S, Ciufolini M, et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One. 2009;4:e7258.
   PubMed Web of Science ®Google Scholar
• Votrient (pazopanib) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; August 2016.
   Google Scholar
• Garner AP, Gozgit JM, Anjum R, et al. Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients. Clin Cancer Res. 2014;20:5745–5755.
   PubMed Web of Science ®Google Scholar
• Caprelsa (vandetanib) [package insert]. Wilmington, DE: AstraZeneca Pharmaceutical LP; July 2016.
   Google Scholar
• Avastin (bevacizumab) [package insert]. San Francisco, CA: Genentech Inc; December 2016.
   Google Scholar
• Bauer S, Duensing A, Demetri GD, et al. KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene. 2007;26:7560–7568.
   PubMed Web of Science ®Google Scholar
• Quattrone A, Wozniak A, Dewaele B, et al. Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors. Mod Pathol. 2014;27:1510–1520.
   PubMed Web of Science ®Google Scholar
• Lai S, Wang G, Cao X, et al. KIT over-expression by p55PIK-PI3K leads to Imatinib-resistance in patients with gastrointestinal stromal tumors. Oncotarget. 2016;7:1367–1379.
   PubMed Web of Science ®Google Scholar
• Lasota J, Felisiak-Golabek A, Wasag B, et al. Frequency and clinicopathologic profile of PIK3CA mutant GISTs: molecular genetic study of 529 cases. Mod Pathol. 2016;29:275–282.
   PubMed Web of Science ®Google Scholar
• Dogan SS, Esmaeli B. Ocular side effects associated with imatinib mesylate and perifosine for gastrointestinal stromal tumor. Hematol Oncol Clin North Am. 2009;23:109–114.
   PubMed Web of Science ®Google Scholar
• Maira S, Pecchi S, Huang A, et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012;11:317–328.
   PubMed Web of Science ®Google Scholar
• Park E, Park J, Han S, et al. NVP-BKM120, a novel PI3K inhibitor, shows synergism with a SAT3 inhibitor in human gastric cancer cells harboring KRAS mutations. Int J Oncol. 2012;40:1259–1266.
   PubMed Web of Science ®Google Scholar
• Van Looy T, Wozniak A, Floris G, et al. Phosphoinositide 3-kinase inhibitors combined with imatinib in patient-derived xenograft models of gastrointestinal stromal tumors: rationale and efficacy. Clin Cancer Res. 2014;20:6071–6082.
   PubMed Web of Science ®Google Scholar
• Fritsch C, Huang A, Chatenay-Rivauday C, et al. Characterization of the novel and specific PI3Ka inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther. 2014;13:1117–1129.
   PubMed Web of Science ®Google Scholar
• Burris HA, Patel MR, Lanasa MC, et al. Activity of TGR-1202, a novel once-daily PI3Kδ inhibitor, in patients with relapsed or refractory hematologic malignancies. J Clin Oncol. 2014;32:[abstract 2513].
   Web of Science ®Google Scholar
• O’Connor OA, Flinn IW, Patel MR, et al. TGR-1202, a novel once daily PI3K-delta inhibitor, demonstrates clinical activity with a favorable safety profile in patients with CLL and B-cell lymphoma. Blood. 2015;126:[abstract 4154].
   Web of Science ®Google Scholar
• Fremin C, Meloche S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol. 2010;3:8.
   PubMed Web of Science ®Google Scholar
• Hostein I, Faur N, Primois C, et al. BRAF mutation status in gastrointestinal stromal tumors. Am J Clin Pathol. 2010;133:141–148.
   PubMed Web of Science ®Google Scholar
• Tafinlar (dabrafenib) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; June 2016.
   Google Scholar
• Rutkowski P, Blank C. Dabrafenib for the treatment of BRAF V600-positive melanoma: a safety evaluation. Expert Opin Drug Saf. 2014;13:1249–1258.
   PubMed Web of Science ®Google Scholar
• King AJ, Arnone MR, Bleam MR, et al. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One. 2013;8:e67583.
   PubMed Web of Science ®Google Scholar
• Falchook G, Trent J, Heinrich M, et al. BRAF mutant gastrointestinal stromal tumor: first report of regression with BRAF inhibitor dabrafenib (GSK2118436) and whole exomic sequencing for analysis of acquired resistance. Oncotarget. 2013;4:310–315.
   PubMed Web of Science ®Google Scholar
• Ran L, Sirota I, Cao Z, et al. Dual lineage inhibition of ETV1 and KIT disrupts the ETV1-KIT feed forward circuit and potentiates imatinib antitumor effect in GIST oncogenesis. Cancer Res. 2014;74:[abstract 3396].
   Web of Science ®Google Scholar
• Lee PA, Wallace E, Marlow A, et al. Preclinical development of ARRY-162, a potent and selective MEK 1/2 inhibitor. Cancer Res. 2010;70:[abstract 2515].
   Web of Science ®Google Scholar
• Demetri GD, Le Cesne A, Von Mehren M, et al. Final results from a phase III study of IPI-504 (retaspimycin hydrochloride) versus placebo in patients (pts) with gastrointestinal stromal tumors (GIST) following failure of kinase inhibitor therapies. Gastrointest Cancers Symp. 2010;[abstract 64]. Available from: http://meetinglibrary.asco.org/content/2285-72
   Google Scholar
• Wagner AJ, Agulnik M, Heinrich MC, et al. Dose-escalation study of a second-generation non-ansamycin HSP90 inhibitor, onalespib (AT13387), in combination with imatinib in patients with metastatic gastrointestinal stromal tumour. Eur J Cancer. 2016;61:94–101.
   PubMed Web of Science ®Google Scholar
• Sawan C, Herceg Z. Histone modifications and cancer. Adv Genet. 2010;70:57–85.
   PubMed Web of Science ®Google Scholar
• West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124:30–39.
   PubMed Web of Science ®Google Scholar
• Bauer S, Hilger RA, Muhlenberg T, et al. Phase I study of panobinostat and imatinib in patients with treatment-refractory metastatic gastrointestinal stromal tumors. Br J Cancer. 2014;110:1155–1162.
   PubMed Web of Science ®Google Scholar
• Istodax (romidepsin) [package insert]. Summit, NJ: Celgene Corporation; July 2016.
   Google Scholar
• Zolinza (vorinostat) [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; December 2015.
   Google Scholar
• Yervoy (ipilimumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb; March 2017.
   Google Scholar
• Opdivo (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb; February 2017.
   Google Scholar
• Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; March 2017.
   Google Scholar
• Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56–61.
   PubMed Web of Science ®Google Scholar
• Seifert AM, Zeng S, Zhang JQ, et al. PD-1/PD-L1 blockade enhances T cell activity and antitumor efficacy of imatinib in gastrointestinal stromal tumors. Clin Cancer Res. 2017;23:454–465.
   Google Scholar
• Balachandran VP, Cavnar MJ, Zeng S, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med. 2011;17:1094–1100.
   PubMed Web of Science ®Google Scholar
• D’Angelo SP, Shoushtari AN, Keohan ML, et al. Combined KIT and CTLA-4 blockade in patients with refractory GIST and other advanced sarcomas: a phase Ib study of dasatinib plus ipilimumab. Clin Cancer Res. cited 2016 Dec;[Epub ahead of print].DOI:10.1158/1078-0432.CCR-16-2349
   PubMed Web of Science ®Google Scholar
• Immunicum. INTUVAX(R). cited. 2017. Mar 2013. Available at http://immunicum.se/technology/intuvax/
   Google Scholar
• Lim S, Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development. 2013;140:3079–3093.
   PubMed Web of Science ®Google Scholar
• Haller F, Gunawan B, Von Heydebreck A, et al. Prognostic role of E2F1 and members of the CDKN2A network in gastrointestinal stromal tumors. Clin Cancer Res. 2005;11:6589–6597.
   PubMed Web of Science ®Google Scholar
• Nannini M, Astolfi A, Urbini M, et al. Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST). BMC Cancer. 2014;14:685,2407-14-685.
   PubMed Web of Science ®Google Scholar
• Parikh K, Cang S, Sekhri A, et al. Selective inhibitors of nuclear export (SINE)- a novel class of anti-cancer agents. J Hematol Oncol. 2014;7:78.
   PubMed Web of Science ®Google Scholar
• Nakayama R, Zhang Y, Anatone A, et al. Preclinical activity of selinexor, an inhibitor of XPO1/CRM1, in sarcoma. Cancer Res. 2015;75:[abstract 1759].
   PubMed Web of Science ®Google Scholar
• Gounder MM, Zer A, Tap WD, et al. A phase 1b study with selinexor, a first in class selective inhibitor of nuclear export (SINE) in patients with advanced sarcoma: an efficacy analysis. J Clin Oncol. 2015;33:[abstract 10569].
   PubMed Web of Science ®Google Scholar
• Gross MI, Demo SD, Dennison JB, et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014;13:890–901.
   PubMed Web of Science ®Google Scholar
• Miettinen M, Wang ZF, Sarlomo-Rikala M, et al. Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol. 2011;35:1712–1721.
   PubMed Web of Science ®Google Scholar
• Edmonson JH, Marks RS, Buckner JC, et al. Contrast of response to dacarbazine, mitomycin, doxorubicin, and cisplatin (DMAP) plus GM-CSF between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas. Cancer Invest. 2002;20:605–612.
   PubMed Web of Science ®Google Scholar
• Maurel J, Martins AS, Poveda A, et al. Imatinib plus low-dose doxorubicin in patients with advanced gastrointestinal stromal tumors refractory to high-dose imatinib. Cancer. 2010;116:3692–3701.
   PubMed Web of Science ®Google Scholar
• Feldman R, Gatalica Z, Reddy SK, et al. Molecularly-guided therapeutic options beyond tyrosine kinase inhibitors (TKIs) for gastrointestinal stromal tumors (GIST). J Clin Oncol. 2015;33:[abstract 58].
   Web of Science ®Google Scholar
• Feldman R, Reddy SK, Gatalica Z, et al. Identification of therapy options for rare and resistant gastrointestinal stromal tumors (GIST). J Clin Oncol. 2015;33:[abstract 10539].
   Web of Science ®Google Scholar
• Akasaka K, Maesawa C, Shibazaki M, et al. Loss of class III beta-tubulin induced by histone deacetylation is associated with chemosensitivity to paclitaxel in malignant melanoma cells. J Invest Dermatol. 2009;129:1516–1526.
   PubMed Web of Science ®Google Scholar
• Corbin KS, Kindler HL, Liauw SL. Considering the role of radiation therapy for gastrointestinal stromal tumor. Onco Targets Ther. 2014;7:713–718.
   PubMed Web of Science ®Google Scholar
• Joensuu H, Eriksson M, Collan J, et al. Radiotherapy for GIST progressing during or after tyrosine kinase inhibitor therapy: A prospective study. Radiother Oncol. 2015;116:233–238.
   PubMed Web of Science ®Google Scholar
• Dalm SU, Bakker IL, De Blois E, et al. 68Ga/177Lu-NeoBOMB1, a novel radiolabeled GRPR antagonist for theranostic use in oncol-ogy. J Nucl Med. 2017;58:293–299.
   Google Scholar
• Shoushtari AN, Van Tine BA, Schwartz GK. Novel treatment targets in sarcoma: more than just the GIST. ASCO Educational Book. 2014. p. e488–95. DOI:10.14694/EdBook_AM.2014.34.e488.
   Google Scholar
• Doyle LA, Hornick JL. Gastrointestinal stromal tumours: from KIT to succinate dehydrogenase. Histopathology. 2014;64:53–67.
   PubMed Web of Science ®Google Scholar
• Mak IWY, Evaniew N, Ghert M. Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res. 2014;6:114–118.
   PubMed Web of Science ®Google Scholar
• Laurie SA, Jonker DJ, Edenfield WJ, et al. A phase 1 dose-escalation study of BBI503, a first-in-class cancer stemness kinase inhibitor in adult patients with advanced solid tumors. J Clin Oncol. 2014;32:[abstract 2527].
   PubMed Web of Science ®Google Scholar
• Palma G, Frasci G, Chirico A, et al. Triple negative breast cancer: looking for the missing link between biology and treatments. Oncotarget. 2015;6:26560–26574.
   PubMed Web of Science ®Google Scholar
• Szekely B, Silber AL, Pusztai L. New therapeutic strategies for triple-negative breast cancer. Oncology (Williston Park). 2017;31:221108.
   PubMed Web of Science ®Google Scholar
• Le Du F, Eckhardt BL, Lim B, et al. Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype? Oncotarget. 2015;6:12890–12908.
   PubMed Web of Science ®Google Scholar
• Poulikakos PI, Zhang C, Bollag G, et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427–430.
   PubMed Web of Science ®Google Scholar
• Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431–435.
   PubMed Web of Science ®Google Scholar
• Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–221.
   PubMed Web of Science ®Google Scholar
• Gasparotto D, Miolo G, Torrisi E, et al. Improved outcome with multimodal treatment and imatinib rechallenge in advanced GIST. Int J Colorectal Dis. 2014;29:639–640.
   PubMed Web of Science ®Google Scholar
• Ordog T, Zornig M, Hayashi Y. Targeting disease persistence in gastrointestinal stromal tumors. Stem Cells Transl Med. 2015;4:702–707.
   PubMed Web of Science ®Google Scholar
• Songdej N, Von Mehren M. GIST treatment options after tyrosine kinase inhibitors. Curr Treat Options Oncol. 2014;15:493–506.
   PubMed Web of Science ®Google Scholar
• DeMatteo R, Chapman S. Immunotherapy drives a paradigm shift toward a new model of treatment. GIST Cancer J. 2014;1:104–109.
   Google Scholar
• Lamba G, Ambrale S, Lee B, et al. Recent advances and novel agents for gastrointestinal stromal tumor (GIST). J Hematol Oncol. 2012;5:21.
   PubMed Web of Science ®Google Scholar