Mp60-17 Therapeutic Resistance Models and Treatment Sequencing in Advanced Prostate Cancer

You have accessJournal of UrologyProstate Cancer: Advanced (Including Drug Therapy) III (MP60)1 May 2024MP60-17 THERAPEUTIC RESISTANCE MODELS AND TREATMENT SEQUENCING IN ADVANCED PROSTATE CANCER Zachary Schaaf, Shu Ning, Alan Lombard, Chengfei Liu, Wei Lou, and Allen Gao Zachary SchaafZachary Schaaf , Shu NingShu Ning , Alan LombardAlan Lombard , Chengfei LiuChengfei Liu , Wei LouWei Lou , and Allen GaoAllen Gao View All Author Informationhttps://doi.org/10.1097/01.JU.0001008804.84010.ec.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Current common treatments for advanced prostate cancer typically belong to one of three major categories: next-generation anti-androgen therapies (NGAT) including enzalutamide, abiraterone acetate, apalutamide, and darolutamide; taxane therapy represented by docetaxel; and PARP inhibitors (PARPi) like olaparib. Although these treatments have shown efficacy and have improved outcomes for many patients, some do not survive due to the emergence of therapeutic resistance. The clinical landscape is further complicated by limited knowledge about how the sequence of treatments impacts the development of therapeutic cross-resistance in CRPC. METHODS: NGAT-resistant (NGAT-R) lines were generated from parental C4-2B cells as described previously by our group with resistance to enzalutamide (MDVR), abiraterone acetate (AbiR), apalutamide (ApaR) and darolutamide (DaroR) through chronic exposure to those therapeutics. Likewise, docetaxel-resistant (TaxR) cells and olaparib-resistant (OlapR) cells were also generated from the C4-2B background through exposure to docetaxel and olaparib, respectively. Cell groups were utilized in growth assays with varying doses of the mentioned xenobiotics to assess relative therapeutic efficacy in each setting. This was followed with RNA sequencing paired with transcriptome analysis to identify major differences in each group. RESULTS: We have developed multiple models of acquired therapeutic resistance cell sublines from C4-2B cells. These include C4-2B MDVR, C4-2B AbiR, C4-2B ApaR, C4-2B DaroR, TaxR, and 2B-olapR, which are resistant to enzalutamide, abiraterone, apalutamide, darolutamide, docetaxel, and olaparib, respectively. These models are instrumental for analyzing gene expression and assessing responses to various treatments. Our findings reveal distinct cross-resistance characteristics among NGAT-resistant cell sublines. Specifically, resistance to enzalutamide induces resistance to abiraterone and vice versa, while maintaining sensitivity to taxanes and olaparib. Conversely, cells with acquired resistance to docetaxel exhibit cross-resistance to both cabazitaxel and olaparib but retain sensitivity to NGATs like enzalutamide and abiraterone. OlapR cells, significantly resistant to olaparib compared to parental cells, are still responsive to NGATs and docetaxel. Moreover, OlapR models display cross-resistance to other clinically relevant PARP inhibitors, including rucaparib, niraparib, and talazoparib. Transcriptomic analyses have revealed a complex network of altered gene expressions that influence signaling pathways, energy metabolism, and apoptotic signaling, pivotal to cancer's evolution and progression. The data indicate that resistance mechanisms are distinct among different drug classes. Notably, NGAT-resistant sublines exhibited a significant downregulation of androgen-regulated genes, contrasting to the stable expression noted in olaparib and docetaxel-resistant sublines. CONCLUSIONS: Our findings suggest the existence of intra cross-resistance within a drug class (i.e., within NGATs or within taxanes, or within PARPi's). These results may have clinical implications by showing that treatments of one class can be sequenced with those from another class, but caution should be taken when sequencing drugs of the same class. Source of Funding: CA253605 (A.C.G), CA 225836 (A.C.G), CA250082 (A.C.G), CA271327 (A.C.G), DOD PC180180 (A.C.G), and the U.S. Department of Veterans Affairs, Office of Research & Development BL&D grant number I01BX004036 (A.C.G), BLR&D Research Career Scientist Award IK6BX005222 (A.C.G). A.C.G is also a Senior Research Career Scientist at VA Northern California Health Care System, Mather, California © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e1007 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Zachary Schaaf More articles by this author Shu Ning More articles by this author Alan Lombard More articles by this author Chengfei Liu More articles by this author Wei Lou More articles by this author Allen Gao More articles by this author Expand All Advertisement PDF downloadLoading ...