Genotoxic antibody-drug conjugates combined with BCL-XL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer
Galina Semenova, Sander B. Frank, Ruth Dumpit, Wanting Han, Ilsa Coleman, Roman Gulati, Canan D. Dirican, Tarana Arman, Jessica Maruwan, Colm Morrissey, Michael C. Haffner, Peter S. Nelson, John K. Lee
Galina Semenova, Sander B. Frank, Ruth Dumpit, Wanting Han, Ilsa Coleman, Roman Gulati, Canan D. Dirican, Tarana Arman, Jessica Maruwan, Colm Morrissey, Michael C. Haffner, Peter S. Nelson, John K. Lee
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Research Article Immunology Oncology

Genotoxic antibody-drug conjugates combined with BCL-XL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive subtype of prostate cancer (PC) without curative treatments. Antibody-drug conjugates (ADCs) emerged as promising cancer therapeutics that selectively deliver cytotoxic agents (payloads) to the tumors. Although ADCs have been successfully applied to treat hematological and solid tumors, ADC monotherapy has not demonstrated durable responses in mCRPC, and mechanisms of PC resistance to ADCs have not been thoroughly investigated. Our study aimed to improve ADC efficacy using an integrated approach for a custom ADC design and multiplexing. To nominate rational combinations of ADC targets and payloads, we (a) examined protein coexpression of 3 clinically relevant surface antigens — B7-H3, PSMA, and STEAP1 — in human mCRPCs and (b) screened established ADC payloads and their combinations in mCRPC cell lines with different molecular backgrounds. Identified synergistic interactions between DNA-damaging payloads and the BCL-XL inhibitor A-1331852 as well as their coordinated induction of the intrinsic apoptosis pathway were evaluated in PC cell lines. Functional relevance between isolated p53 loss and PC responses to 3 genotoxic ADCs — B7-H3–seco-DUBA, PSMA-SG3249, and STEAP1-DXd — and their combinations with A-1331852 were established using genetic knockout models. Lastly, enhanced in vivo antitumor activity of vobramitamab duocarmazine by systemic A-1331852 was shown. Collectively, our findings provide rationale for development of ADC therapies combining genotoxic payloads with BCL-XL inhibitors for mCRPC.

Authors

Galina Semenova, Sander B. Frank, Ruth Dumpit, Wanting Han, Ilsa Coleman, Roman Gulati, Canan D. Dirican, Tarana Arman, Jessica Maruwan, Colm Morrissey, Michael C. Haffner, Peter S. Nelson, John K. Lee

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Figure 3

Screening of ADC payloads in PC cell lines.

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Screening of ADC payloads in PC cell lines. (A) List of cytotoxic agents...
(A) List of cytotoxic agents tried in the drug screen. (B) Relative viability of PC cells exposed to the screen compounds (low dose): 10-deacetyl-7-xylosyl paclitaxel (0.5 μM), PF-06380101 (0.1 nM), mertansine (0.1 nM), DM4 (0.5 nM), ispinesib (0.5 nM), SG3199 (0.1 nM), SJG-136 (0.5 nM), PNU- 159682 (0.1 nM), daunorubicin (hydrochloride) (0.1 μM), DXd (0.1 μM), calicheamicin (0.1 nM), thailanstatin A (0.1 μM), duocarmycin TM (0.1 nM), ansamitocin P-3 (0.5 μM), camptothecin (0.1 μM), dolastatin 10 (0.1 μM), A-1331852 (0.5 μM), α-amanitin (50 nM), β-amanitin (50 nM), FK-866 (50 nM), CHS-828 (5 nM), SN-38 (10 nM), and MMAE (0.1 nM). (B) Normalized responses of C4-2B, 22Rv1, LuCaP176, and MSKCC EF1 to individual payload exposure (low dose). Compounds are organized by the payload class: DDDs (salmon), MDDs (yellow), and IDs (gray). Results are expressed as log10 RLUs, measured via the CellTiter-Glo luminescent assay as a marker of total viability.