Editors' ChoiceCancer therapy

Predicting resistance to KRAS inhibitors

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Science Signaling  14 Jan 2020:
Vol. 13, Issue 614, eaba8405
DOI: 10.1126/scisignal.aba8405

Studies identify common targets for preventing resistance to KRAS inhibitors.

Many cancers have growth-promoting mutations in the gene KRAS. The encoded protein had long been considered “undruggable” until the recent development of inhibitors of one of these mutants, KRAS G12C. Although these new drugs are showing promising results in clinical trials, they are only partially effective, with both innate and adaptive resistance seen in patients. In the Archives of Science Signaling, Lou et al. screened for combination therapies that could enhance the efficacy of the KRAS G12C–targeting drug ARS1620. Using functional genomics that identified pathway rewiring in ARS1620–treated lung and pancreatic cancer cells, the authors found that co-inhibiting the phosphatase SHP2 or the receptor kinases EGFR or FGFR enhanced the drug’s target engagement, and that inhibiting the kinases AXL, PI3K, or CDK4/6 suppressed alternative pathways of tumor cell survival. In a study with a similar goal, Xue et al. report how some lung cancers can bypass ARS1620-induced inhibition of KRAS G12C. Using single-cell RNA sequencing of cell lines and further investigations in mice, the authors identified bypass mechanisms in subsets of quiescent cells. Targeting key proteins, including EGFR and SHP2 but also the kinase AURKA, prevented these pathways from driving new synthesis of KRAS G12C and consequently reactivating KRAS signaling. Together, these studies identify combination therapies that may be able to head off drug resistance and improve survival in patients with KRAS G12C–driven cancers.

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