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<p>When androgen receptor (AR) signaling is suppressed, prostate cancer progression is inhibited; however, many patients eventually relapse, developing castration-resistant prostate cancer (CRPC). Recently, the incidence of double-negative CRPC (DNPC)—which lacks AR and neuroendocrine activity—has increased, yet effective treatments remain unavailable. Our research demonstrated that KRAS has minimal influence during the AR-dependent stages of prostate cancer but significantly activates cancer cells when AR signaling is suppressed. Further investigation revealed that AR inhibition modifies fibroblast growth factor receptor expression in prostate cancer cells. Additionally, CCL2, secreted by AR-inhibited prostate cancer cells, induces FGF8b secretion from stromal cells within the tumor microenvironment, which in turn enhances KRAS activation. A pan-KRAS inhibitor effectively suppressed AR-independent prostate cancer cells by disrupting KRAS-mediated cell survival signaling. This inhibition led to the significant induction of programmed cell death, characterized by the downregulation of the anti-apoptotic protein BCL-xL and the promotion of apoptosis as evidenced by increased cleaved caspase-3 in vivo. These findings highlight KRAS activation, driven by the CRPC microenvironment, as a critical factor in DNPC progression and identify the induction of KRAS-targeted cell death as a promising therapeutic strategy for DNPC.</p>

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Fibroblast-mediated KRAS activation in double-negative prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月2日

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  • Taiki Kamijima,
  • Kouji Izumi,
  • Kaoru Hiratsuka,
  • Takahiro Inaba,
  • Yoshiki Koketsu,
  • Ryunosuke Nakagawa,
  • Ren Toriumi,
  • Shuhei Aoyama,
  • Hiroshi Kano,
  • Tomoyuki Makino,
  • Renato Naito,
  • Suguru Kadomoto,
  • Hiroaki Iwamoto,
  • Hiroshi Yaegashi,
  • Shohei Kawaguchi,
  • Takahiro Nohara,
  • Kazuyoshi Shigehara,
  • Hiroki Nakata,
  • Yohei Saito,
  • Kyoko Nakagawa-Goto,
  • Wen-Jye Lin,
  • Atsushi Mizokami

摘要

When androgen receptor (AR) signaling is suppressed, prostate cancer progression is inhibited; however, many patients eventually relapse, developing castration-resistant prostate cancer (CRPC). Recently, the incidence of double-negative CRPC (DNPC)—which lacks AR and neuroendocrine activity—has increased, yet effective treatments remain unavailable. Our research demonstrated that KRAS has minimal influence during the AR-dependent stages of prostate cancer but significantly activates cancer cells when AR signaling is suppressed. Further investigation revealed that AR inhibition modifies fibroblast growth factor receptor expression in prostate cancer cells. Additionally, CCL2, secreted by AR-inhibited prostate cancer cells, induces FGF8b secretion from stromal cells within the tumor microenvironment, which in turn enhances KRAS activation. A pan-KRAS inhibitor effectively suppressed AR-independent prostate cancer cells by disrupting KRAS-mediated cell survival signaling. This inhibition led to the significant induction of programmed cell death, characterized by the downregulation of the anti-apoptotic protein BCL-xL and the promotion of apoptosis as evidenced by increased cleaved caspase-3 in vivo. These findings highlight KRAS activation, driven by the CRPC microenvironment, as a critical factor in DNPC progression and identify the induction of KRAS-targeted cell death as a promising therapeutic strategy for DNPC.