Fibroblast-mediated KRAS activation in double-negative prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Androgen receptor (AR) signaling suppression inhibits prostate cancer but leads to castration-resistant prostate cancer (CRPC).
• Double-negative CRPC (DNPC), lacking AR and neuroendocrine activity, is increasing with limited treatment options.
• KRAS is minimally influential in AR-dependent prostate cancer but activates cancer cells upon AR suppression.

Purpose of the Study:

• Investigate the role of KRAS in AR-independent prostate cancer progression.
• Identify mechanisms driving KRAS activation in the CRPC microenvironment.
• Evaluate the therapeutic potential of KRAS inhibition in DNPC.

Main Methods:

• Assessed KRAS influence during AR-dependent and AR-suppressed prostate cancer.
• Examined fibroblast growth factor receptor (FGFR) expression changes under AR inhibition.
• Investigated the role of CCL2 and FGF8b in the tumor microenvironment.
• Utilized a pan-KRAS inhibitor to treat AR-independent prostate cancer cells.
• Analyzed programmed cell death markers (BCL-xL, cleaved caspase-3) in vivo.

Main Results:

• AR inhibition enhances KRAS activation in prostate cancer cells.
• CCL2 secreted by AR-inhibited cells induces stromal FGF8b secretion, promoting KRAS activation.
• A pan-KRAS inhibitor effectively suppressed AR-independent prostate cancer cells by disrupting KRAS-mediated survival.
• KRAS inhibition induced significant programmed cell death, downregulating BCL-xL and increasing cleaved caspase-3.

Conclusions:

• KRAS activation, orchestrated by the CRPC microenvironment, is crucial for DNPC progression.
• Targeting KRAS-mediated cell survival signaling offers a promising therapeutic strategy for DNPC.
• Induction of KRAS-targeted cell death presents a viable treatment approach for advanced prostate cancer.