Oncogenic KRAS-associated gene signature defines co-targeting of CDK4/6 and MEK as a viable therapeutic strategy in colorectal cancer

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Abstract

Therapeutic strategies against KRAS mutant colorectal cancers are developed using cell line models, which do not accurately represent the transcriptome driven by oncogenic KRAS in tumors. We sought to identify a KRAS-associated gene signature from colorectal tumors to develop a precise treatment strategy. Integrative analysis of quantitative KRAS mutation detection and matched gene expression profiling in 55 CRC bulk tumors was carried out to define a gene signature enriched in CRC tumors with high KRAS mutation. The KRAS-associated gene signature identified exhibits functional enrichment in cell cycle and mitosis processes, and includes mitotic transcription factor, FOXM1. Combination treatment of CDK4/6 inhibitor Palbociclib and MEK inhibitor PD0325901 was tested in KRAS-mutant, BRAF-mutant CRC, normal colon epithelial lines and xenografts models to determine their efficacy and toxicity and to monitor the changes in the gene signature. Inhibiting CDK4/6, an upstream regulator of FOXM1, and MEK synergistically depleted FOXM1 and KRAS-associated gene signature, suggesting that CDK4/6 and MEK regulate the KRAS gene signature. The combined inhibition of CDK4/6 and MEK elicited a robust therapeutic response in KRAS-dependent and BRAF-mutant CRC, both in vitro and in vivo and this correlated with downregulation of the KRAS-associated gene signature. Our preclinical study demonstrated the efficacy of Palbociclib and PD0325901 combinatorial treatment selectively in KRAS-dependent and BRAF-mutant CRC but not in normal colon epithelial cells. The KRAS-associated gene signature could facilitate the identification of responsive metastatic CRC to this therapeutic strategy in clinical settings.

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