title: KRASmutant tumor subpopulations can subvert durable responses to personalized cancer treatments.
abstract: KRASmutations in colorectal and lung cancers predict failure to respond to therapies that target the EGFR. Significant percentages of patients withKRASwild-type tumors also fail to respond to these therapies. Relapse occurs in patients withKRASwild-type and mutant tumors, with moderately longer progression-free survival in patients withKRASwild-type tumors. Colon and lung tumors frequently carryKRASmutant tumor subpopulations not detected by DNA sequencing. This suggests detected and undetectedKRASmutant subpopulations in colon and lung tumors are undermining the efficacy of anti-EGFR therapies. Therefore, consideration should be given to combining therapies that targetKRASmutant cells with those that downregulate EGFR signaling. As tumors are frequently polyclonal in origin and comprised of distinct clonal populations carrying complementing genetic and/or epigenetic lesions, preclinical models that assess the efficacy of combination therapies in the context of heterogeneous tumor cell populations will be essential for progress in this area.
authors.affiliation: US FDA, National Center for Toxicological Research, Division of Genetic & Molecular Toxicology, HFT-120, 3900 NCTR Road, Jefferson, AR 72079, USA.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Parsons
authors.affiliation: US FDA, National Center for Toxicological Research, Division of Genetic & Molecular Toxicology, HFT-120, 3900 NCTR Road, Jefferson, AR 72079, USA.
authors.forename: Meagan B
authors.initials: MB
authors.lastname: Myers
keywords: ACB–PCR; carcinogenesis; colorectal cancer; epidermal growth factor receptor; mutation detection; non-small-cell lung cancer; oncogene; personalized medicine; polyclonal tumor origin; reactive oxygen species