Silent Mutations Reveal a Novel Treatment for RAS^Q61 Cancers

Despite the extensive study of the role of nonsynonymous mutations in cancer, synonymous (silent) mutations, which do not alter the amino acid sequence, have not been as well studied, with their clinical significance remaining undetermined. Kobayashi and colleagues, thus, sought to address this issue using KRAS^Q61 mutants as a model and showed that treatment with the EGFR inhibitor osimertinib slightly reduced the frequency of the KRAS^Q61K allele, while the allele frequency of other KRAS mutations increased. Concurrent silent mutations present at G60 in KRAS^Q61-mutant cells, however, were significantly increased in response to drug treatment. Clones with KRAS^Q61K mutations, which also lacked this silent mutation, were sensitive to drug treatment as well as demonstrated reduced growth, like that observed with parental cells. Likewise, activated downstream signaling was sustained only in the presence of the double mutant, supporting the need for these silent mutations to promote the oncogenic function of the KRAS^Q61K mutation. Furthermore, using three pan-cancer cohorts, the co-occurrence of these mutations was discovered to be in all cancers that harbor the KRAS^Q61K mutation. Additional analyses revealed single mutants caused alternative splicing, which leads to a truncated or nonfunctional protein due to an introduction of an early stop codon; however, double mutants disrupt this aberrant splicing and allow for production of a functional mutant protein. Another splicing vulnerability related to the exonic splicing enhancer (ESE) was found in KRAS/NRAS/HRAS Q61 mutants, demonstrating their enrichment around these mutations, and investigation into the design of therapies to target these RAS^Q61 mutations established that mutant-specific antisense oligonucleotides, which interfere with the ESE motifs enhanced around the Q61 mutation, were specific for cancer cells containing the Q61 mutation and reduced the growth of RAS-dependent cancer cells both in vitro and in vivo. This study, therefore, exposes the critical nature of silent mutations to the function of oncogenic KRAS^Q61K mutation and presents a targetable vulnerability that has the potential to be extended to other genes that promote tumorigenesis.

Kobayashi Y, Chhoeu C, Li J, Price KS, Kiedrowski LA, Hutchins JL, et al. Silent mutations reveal therapeutic vulnerability in RAS Q61 cancers. Nature 2022;603:335–42.

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