英国苏格兰癌症研究所Owen J. Sansom研究团队揭示了MAPK驱动的上皮细胞可塑性驱动结直肠癌治疗耐药性。2025年11月24日出版的《自然》杂志发表了这项成果。

鉴于KRAS抑制剂的发展和BRAF抑制剂组合的许可，课题组研究人员在晚期临床前CRC模型中询问了对这些药物耐药的关键机制。研究组发现，致癌的MAPK信号传导在体内诱导上皮状态的变化，推动再生/复兴干细胞样群体的采用，而抑制导致Kras和Braf突变肿瘤的快速转录重塑，有利于Wnt相关的典型干细胞表型。这在Kras驱动模型中导致急性治疗耐药性，在Braf驱动模型中导致延迟耐药性。重要的是，当可塑性受到抑制时，例如在早期转移性疾病中，或通过靶向配体依赖性Wnt通路Rnf43突变，可以观察到显著的治疗反应。这解释了之前在BRAF/RNF43共突变患者群体中观察到的对BRAF+EGFR靶向治疗的超级反应，突出了细胞可塑性在治疗反应中的重要性。总之，他们的数据为结直肠癌对MAPK靶向治疗的耐药机制提供了清晰的见解。

此外，旨在控制干细胞命运、限制上皮可塑性或在肿瘤缺乏异质性时进行干预的策略可能会提高这些药物的治疗效果。

据了解，结直肠上皮快速更新，损伤后具有显著的再生能力。在结直肠癌（CRC）中，这种再生能力可以被用来驱动上皮细胞的可塑性。虽然致癌的MAPK信号在结直肠癌中很常见，KRAS（40-50%）和BRAF(10%)1的突变都很频繁，但抑制这一途径通常会导致临床耐药。

附：英文原文

Title: MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance

Author: White, Mark, Mills, Megan L., Millett, Laura M., Gilroy, Kathryn, Hong, Yourae, Zeiger, Lucas B., Simpson, Rosalin J., Corry, Shania M., Ligeza, Amelia, Lannagan, Tamsin R. M., Susanti, Susanti, Ridgway, Rachel A., Yazgili, Ayse S., Grzesiak, Lucile, Amirkhah, Raheleh, Ford, Catriona A., Vlahov, Nikola, Tovell, Hannah, Officer-Jones, Leah, Ficken, Catherine, Pennie, Rachel, Najumudeen, Arafath K., Raven, Alexander, Nasreddin, Nadia, Chauhan, Ekansh, Papanastasiou, Andrew S., Nixon, Colin, Morrison, Vivienne, Jackstadt, Rene, Graham, Janet S., Miller, Crispin J., Ross, Sarah J., Barry, Simon T., Pavet, Valeria, Wilson, Richard H., Le Quesne, John, Dunne, Philip D., Tejpar, Sabine, Leedham, Simon, Campbell, Andrew D., Sansom, Owen J.

Issue&Volume: 2025-11-24

Abstract: The colorectal epithelium is rapidly renewing, with remarkable capacity to regenerate following injury. In colorectal cancer (CRC), this regenerative capacity can be co-opted to drive epithelial plasticity. While oncogenic MAPK signalling in CRC is common, with frequent mutations of both KRAS (40-50%) and BRAF (10%)1, inhibition of this pathway typically drives resistance clinically. Given the development of KRAS inhibitors, and licensing of BRAF inhibitor combinations2-4, we have interrogated key mechanisms of resistance to these agents in advanced preclinical CRC models. We show that oncogenic MAPK signalling induces epithelial state changes in vivo, driving adoption of a regenerative/revival stem like population, while inhibition leads to rapid transcriptional remodeling of both Kras- and Braf-mutant tumours, favoring a Wnt-associated, canonical stem phenotype. This drives acute therapeutic resistance in Kras- and delayed resistance in Braf-driven models. Importantly, where plasticity is restrained, such as in early metastatic disease, or through targeting ligand-dependent Wnt-pathway Rnf43 mutations, marked therapeutic responses are observed. This explains the super response to BRAF+EGFR targeted therapies previously observed in a BRAF/RNF43 co-mutant patient population, highlighting the criticality of cellular plasticity in therapeutic response. Together, our data provides clear insight into the mechanisms underpinning resistance to MAPK targeted therapies in CRC. Moreover, strategies that aim to corral stem cell fate, restrict epithelial plasticity or intervene when tumours lack heterogeneity may improve therapeutic efficacy of these agents.

DOI: 10.1038/s41586-025-09916-w

Source: https://www.nature.com/articles/s41586-025-09916-w