KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer

Investigating therapeutic “outliers” that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D “knockin” mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant allele frequency were more sensitive to MAP kinase inhibition, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment. In a prospectively characterized cohort of patients with advanced cancer, 642 of 1,168 (55%) with KRAS mutations exhibited allelic imbalance. These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer and modulate competitive fitness and MEK dependency. [Display omitted] •Increased oncogenic Kras expression promotes clonal outgrowth of Kras mutant AMLs•Subsequent loss of WT Kras both enhances fitness and confers MEK dependence•Mutant KRAS allelic imbalance modulates MAPK sensitivity in colorectal cancer cells•55% of advanced KRAS mutant cancers exhibit allelic imbalance at the KRAS locus An imbalance in the dosage of mutant and wild-type KRAS allele shapes the trade-off between rapid cancer cell growth and resistance to MEK inhibitor therapy. This imbalance explains the challenges encountered during inhibitor trials.