Kwon Young-Ju, Kim Dong Young, Kim Uk-Il, Kim Song Hyun, Kim Ye-Hyun, Kim Kyungjin, Kim Jae-Sung
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; Radiological and Medico-Oncological Sciences, University of Science and Technology, Seoul, Republic of Korea.
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Biochem Pharmacol. 2025 May;235:116842. doi: 10.1016/j.bcp.2025.116842. Epub 2025 Feb 28.
Mitogen-activated protein kinase (MEK) inhibitors show promise in treating KRAS-mutated cancers, including colorectal cancer (CRC). However, acquired resistance to MEK inhibitors often results in failure of effective treatment in patients with KRAS-mutated CRC. Here, we demonstrated that basroparib overcomes MEK inhibitor resistance in KRAS-G12V- or -G12D-mutated CRC. This basroparib-mediated sensitization was dependent on the KRAS mutation status and was enhanced specifically in KRAS-G12V- or -G12D-mutated cells. Additionally, when combined with MEK inhibitors, basroparib significantly reduced tumor growth in KRAS-G12V-mutated CRC xenograft models, but not in KRAS-G13D-mutated and -wild-type models. Furthermore, basroparib sensitized KRAS-G12V-mutated CRC cells with acquired resistance to MEK inhibitors. Notably, when combined with MEK inhibitors, basroparib not only suppressed tumor regrowth but also prolonged the survival of tumor models with acquired resistance to MEK inhibitors. Mechanistically, basroparib suppressed Wnt-mediated cancer stemness, a bypass mechanism for acquired resistance to MEK inhibitors in KRAS-mutated CRC. This study provides the first preclinical evidence of the relevance of basroparib in treating CRC with acquired resistance to MEK inhibitors due to APC and KRAS mutations, possibly by reducing the Wnt-mediated cancer stemness.
丝裂原活化蛋白激酶（MEK）抑制剂在治疗包括结直肠癌（CRC）在内的KRAS突变型癌症方面显示出前景。然而，对MEK抑制剂产生的获得性耐药常常导致KRAS突变型CRC患者的有效治疗失败。在此，我们证明巴罗帕利布可克服KRAS - G12V或 - G12D突变型CRC中的MEK抑制剂耐药性。这种巴罗帕利布介导的致敏作用取决于KRAS突变状态，并且在KRAS - G12V或 - G12D突变细胞中特异性增强。此外，当与MEK抑制剂联合使用时，巴罗帕利布显著降低了KRAS - G12V突变型CRC异种移植模型中的肿瘤生长，但在KRAS - G13D突变型和野生型模型中则不然。此外，巴罗帕利布使对MEK抑制剂产生获得性耐药的KRAS - G12V突变型CRC细胞致敏。值得注意的是，当与MEK抑制剂联合使用时，巴罗帕利布不仅抑制了肿瘤再生，还延长了对MEK抑制剂产生获得性耐药的肿瘤模型的生存期。从机制上讲，巴罗帕利布抑制了Wnt介导的癌症干性，这是KRAS突变型CRC中对MEK抑制剂产生获得性耐药的一种旁路机制。本研究提供了首个临床前证据，证明巴罗帕利布在治疗因APC和KRAS突变而对MEK抑制剂产生获得性耐药的CRC中的相关性，可能是通过降低Wnt介导的癌症干性实现的。
