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Updated: Oct 30, 2025
Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells
Published on: March 1, 2024
A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential
Sander A L Palit1, Jeroen van Dorp2,3, Daniel Vis2
1Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. s.palit@nki.nl.
Abstract:
Resistance to drugs targeting the androgen receptor (AR) signaling axis remains an important challenge in the treatment of prostate cancer patients. Activation of alternative growth pathways is one mechanism used by cancer cells to proliferate despite treatment, conferring drug resistance. Through a kinome-centered CRISPR-Cas9 screen in CWR-R1 prostate cancer cells, we identified activated BRAF signaling as a determinant for enzalutamide resistance. Combined pharmaceutical targeting of AR and MAPK signaling resulted in strong synergistic inhibition of cell proliferation. The association between BRAF activation and enzalutamide resistance was confirmed in two metastatic prostate cancer patients harboring activating mutations in the BRAF gene, as both patients were unresponsive to enzalutamide. Our findings suggest that co-targeting of the MAPK and AR pathways may be effective in patients with an activated MAPK pathway, particularly in patients harboring oncogenic BRAF mutations. These results warrant further investigation of the response to AR inhibitors in BRAF-mutated prostate tumors in clinical settings.
Insights
Drug resistance in prostate cancer is a major challenge. Targeting both androgen receptor (AR) and MAPK pathways, especially BRAF mutations, shows promise for overcoming enzalutamide resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Androgen receptor (AR) signaling is a key target in prostate cancer treatment.
- Drug resistance, often through alternative growth pathways, limits treatment efficacy.
- Enzalutamide resistance is a significant clinical challenge in advanced prostate cancer.
Purpose of the Study:
- To identify mechanisms of enzalutamide resistance in prostate cancer.
- To investigate the role of activated signaling pathways in conferring drug resistance.
- To evaluate combination therapies targeting AR and alternative pathways.
Main Methods:
- Utilized a kinome-centered CRISPR-Cas9 screen in CWR-R1 prostate cancer cells.
- Performed pharmaceutical targeting of AR and MAPK signaling pathways.
- Analyzed patient data from metastatic prostate cancer cases with BRAF mutations.
Main Results:
- Activated BRAF signaling was identified as a determinant of enzalutamide resistance.
- Combined targeting of AR and MAPK signaling synergistically inhibited cell proliferation.
- Two metastatic prostate cancer patients with BRAF mutations showed unresponsiveness to enzalutamide.
Conclusions:
- Co-targeting MAPK and AR pathways may be effective for prostate cancer patients with activated MAPK signaling, particularly those with BRAF mutations.
- BRAF mutations are associated with enzalutamide resistance.
- Further clinical investigation is warranted for AR inhibitors in BRAF-mutated prostate tumors.
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