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Direct Co-Targeting of Bcl-xL and Mcl-1 Exhibits Synergistic Effects in AR-V7-Expressing CRPC Models
Benjamin C Brim1, Andres F Leon1, Erica L Beatson1
1Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Abstract:
There is an unmet need to develop novel treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC). Patients often develop resistance to next-generation hormonal therapies that target the androgen receptor (AR) axis (e.g., abiraterone and enzalutamide). A splice variant of AR, AR-V7, is associated with resistance to these inhibitors as well as mCRPC progression and poor prognoses. We embarked upon a high-throughput screen to identify synergistic combinations of targeted therapies using two CRPC cell lines, LNCaP95 and VCaP-CR. Combinations targeting BCL2L1 (Bcl-xL) (A-1331852 and navitoclax) and MCL1 (S63845) synergistically decreased cell viability and induced apoptotic activity via cleavage of PARP, caspase 3, and caspase 7 across AR-V7-expressing CRPC cell lines (LNCaP95, VCaP-CR, and 22Rv1) and a patient-derived organoid model (LuCaP 167CR). We also explored the use of a Bcl-xL-specific proteolysis-targeting chimera degrader (PROTAC) to minimize platelet toxicity associated with Bcl-xL inhibitors. We showed similar synergistic efficacy with the Bcl-xL-targeting PROTAC in combination with S63845 in the three-dimensional spheroid models. Our findings support further preclinical development of Bcl-xL and Mcl-1 inhibitors for mCRPC.
Significance:
Using an unbiased, combinatorial, high-throughput drug screen, we identified the combination of co-targeting Bcl-xL and Mcl-1 to be highly synergistic across AR-V7-expressing CRPC models. We showed efficacy in higher-order models through validation across in vitro models spanning two-dimensional cell culture, three-dimensional cell culture, and a patient-derived organoid model. These findings identify a promising therapeutic strategy for patients with AR-V7-expressing CRPC.
Insights
Targeting Bcl-xL and Mcl-1 shows promise for treating advanced prostate cancer. Combining these therapies effectively reduced cancer cell viability in models resistant to standard treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) presents a significant unmet need for novel therapies.
- Resistance to androgen receptor (AR) axis inhibitors, such as abiraterone and enzalutamide, is a major clinical challenge.
- The AR splice variant AR-V7 is linked to treatment resistance, disease progression, and poor prognosis in mCRPC.
Purpose of the Study:
- To identify synergistic drug combinations for treating mCRPC, particularly in AR-V7-expressing models.
- To evaluate the efficacy of targeting BCL2L1 (Bcl-xL) and MCL1 in preclinical mCRPC models.
- To explore the potential of Bcl-xL-targeting PROTACs in combination therapy for mCRPC.
Main Methods:
- Conducted a high-throughput drug screen using two CRPC cell lines (LNCaP95 and VCaP-CR).
- Tested combinations of Bcl-xL inhibitors (A-1331852, navitoclax) and an MCL1 inhibitor (S63845).
- Validated findings in AR-V7-expressing cell lines (LNCaP95, VCaP-CR, 22Rv1) and a patient-derived organoid model (LuCaP 167CR).
- Investigated a Bcl-xL-specific PROTAC in combination with S63845 in 3D spheroid models.
Main Results:
- Co-targeting Bcl-xL and Mcl-1 demonstrated synergistic reduction in cell viability and induced apoptosis across multiple AR-V7-expressing CRPC models.
- Apoptotic activity was confirmed by cleavage of PARP, caspase 3, and caspase 7.
- The Bcl-xL-targeting PROTAC, in combination with S63845, showed similar synergistic efficacy in 3D models, suggesting reduced toxicity potential.
Conclusions:
- The combination of Bcl-xL and Mcl-1 inhibition is a highly synergistic strategy for AR-V7-expressing mCRPC.
- This therapeutic approach has shown efficacy across various preclinical models, including 2D, 3D, and patient-derived organoids.
- Further preclinical development of Bcl-xL and Mcl-1 inhibitors is warranted for mCRPC treatment.
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