MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance.
White M., Mills ML., Millett LM., Gilroy K., Hong Y., Zeiger LB., Simpson RJ., Corry SM., Ligeza A., Lannagan TRM., Susanti S., Ridgway RA., Yazgili AS., Grzesiak L., Amirkhah R., Ford CA., Vlahov N., Tovell H., Officer-Jones L., Ficken C., Pennie R., Najumudeen AK., Raven A., Nasreddin N., Chauhan E., Papanastasiou AS., Nixon C., Morrison V., Jackstadt R., Graham JS., Miller CJ., Ross SJ., Barry ST., Pavet V., Wilson RH., Le Quesne J., Dunne PD., Tejpar S., Leedham S., Campbell AD., Sansom OJ.
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.