Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer

Abstract

Mutations in the KRAS oncogene represent one of the most prevalent genetic alterations in colorectal cancer (CRC), the third leading cause of cancer-related death in the US. In addition to their well-characterized function in driving tumor progression, KRAS mutations have been recognized as a critical determinant of the therapeutic response of CRC. Recent studies demonstrate that KRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor (EGFR) targeting antibodies, including cetuximab and panitumumab. Acquired resistance to the anti-EGFR therapy was found to be associated with enrichment of KRAS-mutant tumor cells. However, the underlying molecular mechanism of mutant-KRAS-mediated therapeutic resistance has remained unclear. Despite intensive efforts, directly targeting mutant KRAS has been largely unsuccessful. This review summarizes the recent advances in understanding the biological function of KRAS mutations in determining the therapeutic response of CRC, highlighting several recently developed agents and strategies for targeting mutant KRAS, such as synthetic lethal interactions.

Keywords: EGFR; KRAS; colorectal cancer; synthetic lethality; targeted therapy.

Figure 1

EGFR-induced and KRAS-mediated signaling pathways. (A) Activation of EGFR upon ligand binding and its subsequent auto-phosphorylation create a docking site for the SOS/GRB2 complex, resulting in nucleotide exchange by SOS and the GTP-bound form of KRAS. KRAS then signals through the RAF/MEK/ERK and PI3K/AKT cascades to promote cell growth and suppress apoptosis. (B) Anti-EGFR antibodies, including cetuximab and panitumumab, bind to EGFR and prevent ligand binding and subsequent KRAS activation, leading to growth suppression and cell death due to the inhibition of the RAF/MEK/ERK and PI3K/AKT pathways. Mutant KRAS can override the effect of anti-EGFR antibodies leading to cell growth and survival.

Figure 2

Mutant-KRAS-mediated synthetic lethality. While a mutation in KRAS or gene X alone is insufficient to kill cells, a combination of mutations in these two genes can lead to cell death, resulting in synthetic lethality. Therefore, specific targeting of mutant KRAS can be achieved indirectly by targeting gene X.