Sensitivities and Dependencies of Mutant Colorectal Cancer Cell Lines with or without Mutations for Discovery of Vulnerabilities with Therapeutic Potential.

Colorectal cancer represents a common malignancy and remains incurable in the metastatic stage. Identification of molecular alterations that are present in colorectal cancer has led to the introduction of targeted therapies that improve outcomes. and mutations are observed in a subset of colorectal cancers. Colorectal cancers bearing mutations may be treated with specific BRAF inhibitors. These drugs benefit patients with mutant colorectal cancers but responses are rather brief, and progression is the rule. In contrast, no PI3K inhibitors have proven successful yet in the disease. Thus, new treatments to supplement the currently available drugs would be welcome to further improve survival. Profiled colorectal cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) were examined for and mutations and were interrogated for molecular characteristics and concomitant alterations that mirror clinical sample alterations. The Genomics of Drug Sensitivity in Cancer (GDSC) project was used for determination of drug sensitivities of mutated colorectal cell lines with or without concomitant mutations. The Cancer Dependency Map project served as the basis for identification of molecular dependencies and vulnerabilities in these cell lines. CCLE includes 84 colorectal cancer cell lines, which recapitulate the molecular landscape of colorectal cancer. Of these, 23 and 24 cell lines possess and mutations, respectively. Seven mutant cell lines have V600E mutations and 14 mutant cell lines have hotspot helical or kinase domain mutations. V600E mutant cell lines with or without hotspot mutations are heterogeneous in their MSI status and mimic colorectal cancer tissues in other prevalent abnormalities including and mutations. Essential genes for survival include , , and pyrimidine metabolism enzyme . Besides mutations, BRAF inhibitor sensitivity in colorectal cancer cell lines is conferred by mutations and locus loss. Colorectal cancer cell lines bearing the frequent and mutations present many alterations of the parental cancer tissue. Described vulnerabilities represent leads for therapeutic exploration in colorectal cancers with the corresponding alterations.