Dynamic transitioning between MAPK-driven and WNT-driven cell states drives intestinal cancer and shapes therapy response

Rákkutatás · Colorectal cancer · KRAS

KRAS mutations drive a regenerative state that antagonizes Lgr5⁺ intestinal stem cells, but tumor initiation requires a WNT‑driven stem‑like state; these plastic states also shape drug response, underscoring the need to target both MAPK and WNT pathways in colorectal cancer.

Colorectal cancer (CRC) frequently harbors activating mutations in the WNT and MAPK pathways. While KRAS mutations alone can drive tumor initiation in many tissues, they are insufficient in the intestine. Leveraging allele‑specific properties of RAS, we developed a mouse model to investigate MAPK hyperactivation. Here we show that KRAS mutations drive a regenerative state while antagonizing the Lgr5⁺ intestinal stem cell state; however, this regenerative state cannot initiate tumorigenesis. Instead, tumor initiation requires a stem‑like state dependent on mutational activation of the WNT pathway. We identify two aberrant states – a WNT‑driven stem‑like state for tumor initiation and MAPK‑driven transit‑amplifying‑like state for tumor growth. These plastic states, essential for tumorigenesis, also impact drug response, potentially explaining lower response rates and shorter duration of response to KRAS‑G12C inhibitors in CRC compared to non‑small cell lung cancer. These findings highlight the need to target both pathways and their associated cell states for effective CRC treatment.

Understanding the distinct MAPK‑driven and WNT‑driven cell states uncovers why KRAS‑G12C inhibitors show limited efficacy in CRC versus non‑small cell lung cancer, and highlights a dual‑pathway therapeutic strategy for better clinical outcomes.

Bizonyítékszint: Klinikai vizsgálat. Formális klinikai vizsgálati eredmény.

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