Oncogenic
mutations of Ras at codons 12, 13, or 61, that render
the protein constitutively active, are found in ∼16% of all
cancer cases. Among the three major Ras isoforms, KRAS is the most
frequently mutated isoform in cancer. Each Ras isoform and tumor type
displays a distinct pattern of codon-specific mutations. In colon
cancer, KRAS is typically mutated at codon 12, but a significant fraction
of patients have mutations at codon 13. Clinical data suggest different
outcomes and responsiveness to treatment between these two groups.
To investigate the differential effects upon cell status associated
with KRAS mutations we performed a quantitative analysis of the proteome
and phosphoproteome of isogenic SW48 colon cancer cell lines in which
one allele of the endogenous gene has been edited to harbor specific
KRAS mutations (G12V, G12D, or G13D). Each mutation generates a distinct
signature, with the most variability seen between G13D and the codon
12 KRAS mutants. One notable example of specific up-regulation in
KRAS codon 12 mutant SW48 cells is provided by the short form of the
colon cancer stem cell marker doublecortin-like Kinase 1 (DCLK1) that
can be reversed by suppression of KRAS.