Heterogeneity in RAS mutations: One size does not fit all

Abstract

Although oncogenic driver mutations in RAS occur in 20% of cancers, heterogeneity in the biologic outputs of different RAS mutants has hampered efforts to develop effective treatments for RAS-mutated cancers. In this issue of Science Signaling, Huynh et al. show that even among KRAS^Q61 mutants, the specific amino acid that is substituted substantially affects mutant KRAS biologic activity and oncogenicity.

Fig. 1.. Heterogeneity in the biologic activity of mutant RAS exists at multiple levels.

(A) Mutant RAS family members show differential sensitivities to FTIs and differential transduction to RAF-MEK-ERK (1, 2) versus PI3K-AKT (1) pathways. (B) In KRAS, hotspot mutants use different mechanisms to alter GTP/GDP cycling (3) and increase RAS^GTP levels. These differences affect both sensitivity to proximal RTK pathway inhibitors (4) and the extent of ERK activation (5, 7, 10). Increasing ERK signaling enhances oncogenicity in G13 and G12 mutants but may induce oncogenic stress in Q61 mutants to limit oncogenicity (–7, 10). (C) Focusing further still on Q61 specifically, the various KRAS^Q61 mutant alleles show relative abundancies that can be classified as common (Q61H, Q61L, and Q61R), less common (Q61K), or rare (Q61E and Q61P) (7). Expression of the common Q61 mutants induces transformation by increasing KRAS-dependent cell metabolism and destabilizing actin stress fibers (7), whereas rare Q61P/Q61E mutants are nontransforming (7). Although Q61K is also transforming, its expression is inhibited by a rare cryptic splice donor site and requires a silent (G60G) co-mutation to be expressed (8). These defects in either expression (Q61K) or biologic activity (Q61P/Q61E) help explain why these Q61 mutant alleles occur in cancers less frequently than would be predicted on the basis of mutational spectra of each cancer type.