BET inhibitors in metastatic prostate cancer: therapeutic implications and rational drug combinations

References

• Filippakopoulos P, Picaud S, Mangos M, et al. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell. 2012;149(1):214–231.
   PubMed Web of Science ®Google Scholar
• Rahman S, Sowa ME, Ottinger M, et al. The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol Cell Biol. 2011;31(13):2641–2652.
   PubMed Web of Science ®Google Scholar
• Itzen F, Greifenberg AK, Bosken CA, et al. Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation. Nucleic Acids Res. 2014;42(12):7577–7590.
   PubMed Web of Science ®Google Scholar
• Yang Z, Yik JH, Chen R, et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Molecular Cell. 2005;19(4):535–545.
   PubMed Web of Science ®Google Scholar
• Padmanabhan B, Mathur S, Manjula R, et al. Bromodomain and extra-terminal (BET) family proteins: new therapeutic targets in major diseases. J Biosci. 2016;41(2):295–311.
   PubMed Web of Science ®Google Scholar
• Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904–917.
   PubMed Web of Science ®Google Scholar
• Bernard D, Pourtier-Manzanedo A, Gil J, et al. Myc confers androgen-independent prostate cancer cell growth. J Clin Invest. 2003;112(11):1724–1731.
   PubMed Web of Science ®Google Scholar
• Gao L, Schwartzman J, Gibbs A, et al. Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation. PloS One. 2013;8(5):e63563.
   PubMed Web of Science ®Google Scholar
• Tomlins SA, Mehra R, Rhodes DR, et al. Integrative molecular concept modeling of prostate cancer progression. Nat Genet. 2007;39(1):41–51.
   PubMed Web of Science ®Google Scholar
• Nadiminty N, Tummala R, Liu C, et al. NF-kappaB2/p52:c-Myc:hnRNPA1 pathway regulates expression of androgen receptor splice variants and enzalutamide sensitivity in prostate cancer. Mol Cancer Ther. 2015;14(8):1884–1895.
   PubMed Web of Science ®Google Scholar
• Wyce A, Degenhardt Y, Bai Y, et al. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget. 2013;4(12):2419–2429.
   PubMed Web of Science ®Google Scholar
• Asangani IA, Dommeti VL, Wang X, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510(7504):278–282.
   PubMed Web of Science ®Google Scholar
• Dai X, Gan W, Li X, et al. Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nat Med. 2017;23(9):1063–1071.
   PubMed Web of Science ®Google Scholar
• Janouskova H, El Tekle G, Bellini E, et al. Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors. Nat Med. 2017;23(9):1046–1054.
   PubMed Web of Science ®Google Scholar
• Blattner M, Liu D, Robinson BD, et al. SPOP mutation drives prostate tumorigenesis in vivo through coordinate regulation of PI3K/mTOR and AR signaling. Cancer Cell. 2017;31(3):436–451.
   PubMed Web of Science ®Google Scholar
• Amorim S, Stathis A, Gleeson M, et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol. 2016;3(4):e196–204.
   PubMed Web of Science ®Google Scholar
• Antonarakis ES, Lu C, Luber B, et al. Splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol. 2015;1(5):582–591.
   PubMed Web of Science ®Google Scholar
• Scher HI, Lu D, Schreiber NA, et al. Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol. 2016;2(11):1441–1449.
   PubMed Web of Science ®Google Scholar
• Zhu J, Blenis J, Yuan J. Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc Natl Acad Sci USA. 2008;105(18):6584–6589.
   PubMed Web of Science ®Google Scholar
• Voeller HJ, Truica CI, Gelmann EP. Beta-catenin mutations in human prostate cancer. Cancer Res. 1998;58(12):2520–2523.
   PubMed Web of Science ®Google Scholar
• Miyamoto DT, Zheng Y, Wittner BS, et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science. 2015;349(6254):1351–1356.
   PubMed Web of Science ®Google Scholar
• Annala M, Struss WJ, Warner EW, et al. Treatment outcomes and tumor loss of heterozygosity in Germline DNA repair-deficient prostate cancer. Eur Urol. 2017;72(1):34–42.
   PubMed Web of Science ®Google Scholar
• Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138–148.
   PubMed Web of Science ®Google Scholar
• de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995–2005.
   PubMed Web of Science ®Google Scholar
• Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–1197.
   PubMed Web of Science ®Google Scholar
• Beer TM, Armstrong AJ, Rathkopf DE, et al. The PI. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014.
   Web of Science ®Google Scholar
• Maughan BL, Luber B, Nadal R, et al. Comparing sequencing of abiraterone and enzalutamide in men with metastatic castration-resistant prostate cancer: a retrospective study. Prostate. 2017;77(1):33–40.
   PubMed Web of Science ®Google Scholar
• Noonan KL, North S, Bitting RL, et al. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol. 2013;24(7):1802–1807.
   PubMed Web of Science ®Google Scholar
• Schrader AJ, Boegemann M, Ohlmann CH, et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol. 2014;65(1):30–36.
   PubMed Web of Science ®Google Scholar
• Dehm SM, Schmidt LJ, Heemers HV, et al. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 2008;68(13):5469–5477.
   PubMed Web of Science ®Google Scholar
• Hu R, Dunn TA, Wei S, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69(1):16–22.
   PubMed Web of Science ®Google Scholar
• Antonarakis ES, Armstrong AJ, Dehm SM, et al. Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting. Prostate Cancer Prostatic Dis. 2016;19(3):231–241.
   PubMed Web of Science ®Google Scholar
• Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028–1038.
   PubMed Web of Science ®Google Scholar
• Antonarakis ES, Lu C, Luber B, et al. Clinical significance of androgen receptor splice variant-7 mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clinical Oncol. 2017;35:19:2149–2156.
   Web of Science ®Google Scholar
• Chan SC, Selth LA, Li Y, et al. Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies. Nucleic Acids Res. 2015;43(12):5880–5897.
   PubMed Web of Science ®Google Scholar
• Asangani IA, Wilder-Romans K, Dommeti VL, et al. Enhance efficacy and disrupt resistance to AR antagonists in the treatment of prostate cancer. Molecular Cancer Res MCR. 2016;14(4):324–331.
   PubMed Web of Science ®Google Scholar
• McMenamin ME, Soung P, Perera S, et al. Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res. 1999;59(17):4291–4296.
   PubMed Web of Science ®Google Scholar
• Hopkins BD, Hodakoski C, Barrows D, et al. PTEN function: the long and the short of it. Trends Biochem Sci. 2014;39(4):183–190.
   PubMed Web of Science ®Google Scholar
• Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011;19(5):575–586.
   PubMed Web of Science ®Google Scholar
• Crumbaker M, Khoja L, Joshua AMAR. Signaling and the PI3K pathway in prostate cancer. Cancers. 2017;9:4.
   Web of Science ®Google Scholar
• Zafarana G, Ishkanian AS, Malloff CA, et al. Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. Cancer. 2012;118(16):4053–4062.
   PubMed Web of Science ®Google Scholar
• Lapointe J, Li C, Giacomini CP, et al. Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. Cancer Res. 2007;67(18):8504–8510.
   PubMed Web of Science ®Google Scholar
• Gera JF, Mellinghoff IK, Shi Y, et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem. 2004;279(4):2737–2746.
   PubMed Web of Science ®Google Scholar
• Hubbard GK, Mutton LN, Khalili M, et al. Combined MYC activation and PTEN loss are sufficient to create genomic instability and lethal metastatic prostate cancer. Cancer Res. 2016;76(2):283–292.
   PubMed Web of Science ®Google Scholar
• Stratikopoulos EE, Dendy M, Szabolcs M, et al. Clamp inhibition of PI3K signaling and overcome resistance to therapy. Cancer Cell. 2015;27(6):837–851.
   PubMed Web of Science ®Google Scholar
• Song LN, Herrell R, Byers S, et al. Beta-catenin binds to the activation function 2 region of the androgen receptor and modulates the effects of the N-terminal domain and TIF2 on ligand-dependent transcription. Mol Cell Biol. 2003;23(5):1674–1687.
   PubMed Web of Science ®Google Scholar
• Truica CI, Byers S, Gelmann EP. Beta-catenin affects androgen receptor transcriptional activity and ligand specificity. Cancer Res. 2000;60(17):4709–4713.
   PubMed Web of Science ®Google Scholar
• Yang F, Li X, Sharma M, et al. Linking beta-catenin to androgen-signaling pathway. J Biol Chem. 2002;277(13):11336–11344.
   PubMed Web of Science ®Google Scholar
• Asem MS, Buechler S, Wates RB, et al. Wnt5a signaling in cancer. Cancers. 2016;8:9.
   Web of Science ®Google Scholar
• Rathert P, Roth M, Neumann T, et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature. 2015;525(7570):543–547.
   PubMed Web of Science ®Google Scholar
• Fong CY, Gilan O, Lam EY, et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature. 2015;525(7570):538–542.
   PubMed Web of Science ®Google Scholar
• Alghamdi S, Khan I, Beeravolu N, et al. BET protein inhibitor JQ1 inhibits growth and modulates WNT signaling in mesenchymal stem cells. Stem Cell Res Ther. 2016;7:22.
   PubMed Web of Science ®Google Scholar
• Iglehart JD, Silver DP. Synthetic lethality–a new direction in cancer-drug development. N Engl J Med. 2009;361(2):189–191.
   PubMed Web of Science ®Google Scholar
• Teply BA, Antonarakis ES. Treatment strategies for DNA repair-deficient prostate cancer. Expert Rev Clin Pharmacol. 2017;10(8):889–898.
   PubMed Web of Science ®Google Scholar
• Cancer Genome Atlas Research N. The molecular taxonomy of primary prostate cancer. Cell. 2015;163(4):1011–1025.
   PubMed Web of Science ®Google Scholar
• Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–1228.
   PubMed Web of Science ®Google Scholar
• Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443–453.
   PubMed Web of Science ®Google Scholar
• Antonarakis ES. Germline DNA repair mutations and response to hormonal therapy in advanced prostate cancer. Eur Urol. 2017;72(1):43–44.
   PubMed Web of Science ®Google Scholar
• Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697–1708.
   PubMed Web of Science ®Google Scholar
• Yang L, Zhang Y, Shan W. et al., Repression of BET activity sensitizes homologous recombination-proficient cancers to PARP inhibition. Sci Transl Med, 2017. 9(400).
   Google Scholar
• Floyd SR, Pacold ME, Huang Q, et al. The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature. 2013;498(7453):246–250.
   PubMed Web of Science ®Google Scholar
• Wang L, Xie L, Ramachandran S, et al. Non-canonical bromodomain within DNA-PKcs promotes DNA damage response and radioresistance through recognizing an IR-induced acetyl-lysine on H2AX. Chem Biol. 2015;22(7):849–861.
   PubMedGoogle Scholar