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000306549 1001_ $$00000-0002-6309-3254$$aWhite, Mark$$b0
000306549 245__ $$aMAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance.
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000306549 520__ $$aThe colorectal epithelium is rapidly renewing, with remarkable capacity to regenerate following injury. In colorectal cancer (CRC), this regenerative capacity can be co-opted to drive epithelial plasticity. While oncogenic MAPK signalling in CRC is common, with frequent mutations of both KRAS (40-50%) and BRAF (10%)1, inhibition of this pathway typically drives resistance clinically. Given the development of KRAS inhibitors, and licensing of BRAF inhibitor combinations2-4, we have interrogated key mechanisms of resistance to these agents in advanced preclinical CRC models. We show that oncogenic MAPK signalling induces epithelial state changes in vivo, driving adoption of a regenerative/revival stem like population, while inhibition leads to rapid transcriptional remodeling of both Kras- and Braf-mutant tumours, favoring a Wnt-associated, canonical stem phenotype. This drives acute therapeutic resistance in Kras- and delayed resistance in Braf-driven models. Importantly, where plasticity is restrained, such as in early metastatic disease, or through targeting ligand-dependent Wnt-pathway Rnf43 mutations, marked therapeutic responses are observed. This explains the super response to BRAF+EGFR targeted therapies previously observed in a BRAF/RNF43 co-mutant patient population, highlighting the criticality of cellular plasticity in therapeutic response. Together, our data provides clear insight into the mechanisms underpinning resistance to MAPK targeted therapies in CRC. Moreover, strategies that aim to corral stem cell fate, restrict epithelial plasticity or intervene when tumours lack heterogeneity may improve therapeutic efficacy of these agents.
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000306549 7001_ $$00009-0000-0922-7912$$aMills, Megan L$$b1
000306549 7001_ $$00009-0000-7596-4275$$aMillett, Laura M$$b2
000306549 7001_ $$00000-0003-4607-194X$$aGilroy, Kathryn$$b3
000306549 7001_ $$00000-0001-6683-433X$$aHong, Yourae$$b4
000306549 7001_ $$00000-0002-8712-3112$$aZeiger, Lucas B$$b5
000306549 7001_ $$00009-0001-8571-7275$$aSimpson, Rosalin J$$b6
000306549 7001_ $$aCorry, Shania M$$b7
000306549 7001_ $$00009-0006-9075-3138$$aLigeza, Amelia$$b8
000306549 7001_ $$00000-0002-8206-8898$$aLannagan, Tamsin R M$$b9
000306549 7001_ $$00000-0001-9704-5157$$aSusanti, Susanti$$b10
000306549 7001_ $$00000-0003-0198-8244$$aRidgway, Rachel A$$b11
000306549 7001_ $$00000-0001-8485-9653$$aYazgili, Ayse S$$b12
000306549 7001_ $$00000-0002-7351-2045$$aGrzesiak, Lucile$$b13
000306549 7001_ $$00000-0003-3494-271X$$aAmirkhah, Raheleh$$b14
000306549 7001_ $$00000-0003-3991-6369$$aFord, Catriona A$$b15
000306549 7001_ $$00009-0002-8649-6109$$aVlahov, Nikola$$b16
000306549 7001_ $$00000-0002-2473-7256$$aTovell, Hannah$$b17
000306549 7001_ $$00000-0002-3690-2386$$aOfficer-Jones, Leah$$b18
000306549 7001_ $$00000-0003-4764-210X$$aFicken, Catherine$$b19
000306549 7001_ $$00009-0001-4796-7388$$aPennie, Rachel$$b20
000306549 7001_ $$00000-0002-3764-5721$$aNajumudeen, Arafath K$$b21
000306549 7001_ $$00000-0003-4409-9543$$aRaven, Alexander$$b22
000306549 7001_ $$00000-0002-3025-6213$$aNasreddin, Nadia$$b23
000306549 7001_ $$00000-0002-1096-0625$$aChauhan, Ekansh$$b24
000306549 7001_ $$00000-0002-8888-0633$$aPapanastasiou, Andrew S$$b25
000306549 7001_ $$00000-0002-8085-2160$$aNixon, Colin$$b26
000306549 7001_ $$00009-0009-1022-8969$$aMorrison, Vivienne$$b27
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000306549 7001_ $$00000-0002-2048-2698$$aGraham, Janet S$$b29
000306549 7001_ $$00000-0003-4341-1283$$aMiller, Crispin J$$b30
000306549 7001_ $$00000-0001-8759-1728$$aRoss, Sarah J$$b31
000306549 7001_ $$00000-0002-8511-0588$$aBarry, Simon T$$b32
000306549 7001_ $$00000-0002-4472-6503$$aPavet, Valeria$$b33
000306549 7001_ $$00000-0001-8018-7730$$aWilson, Richard H$$b34
000306549 7001_ $$00000-0003-3552-7446$$aLe Quesne, John$$b35
000306549 7001_ $$00000-0001-9160-283X$$aDunne, Philip D$$b36
000306549 7001_ $$00000-0003-3281-8643$$aTejpar, Sabine$$b37
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000306549 7001_ $$00000-0003-3930-1276$$aCampbell, Andrew D$$b39
000306549 7001_ $$00000-0001-9540-3010$$aSansom, Owen J$$b40
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