Activation of the DNA damage response by wild-type RAS contributes to mutant KRAS-driven oncogenesis.
Major finding: Activation of the DNA damage response by wild-type RAS contributes to mutant KRAS-driven oncogenesis.
Concept: Wild-type HRAS activates the DNA damage checkpoint by antagonizing MAPK/AKT-mediated CHK1 inhibition.
Impact: Inhibition of HRAS or CHK1 may sensitize KRAS-mutant tumors to genotoxic chemotherapy.
Mutation of the RAS genes (HRAS, NRAS, and KRAS) occurs frequently in cancer and leads to activation of multiple signaling pathways that promote tumorigenesis. Oncogenic mutations in KRAS are sufficient to drive tumor formation in vivo, but recent work suggests that the remaining wild-type HRAS and NRAS proteins may contribute to tumor growth, prompting Grabocka and colleagues to investigate the underlying mechanisms. Depletion of wild-type HRAS or NRAS specifically inhibited proliferation of KRAS-mutant cells in association with delayed mitotic progression and mitotic defects suggestive of damaged DNA. Indeed, silencing of HRAS led to increased DNA damage and abrogation of the G2/M cell-cycle checkpoint, which is required to provide cells adequate time to repair damaged DNA prior to entering mitosis. Recent evidence suggests that KRAS effector pathways may bypass antiproliferative responses by inactivating the DNA damage kinase CHK1, leading the authors to hypothesize that wild-type HRAS may reinforce DNA damage checkpoint control by antagonizing mutant KRAS-driven signaling. Indeed, HRAS depletion enhanced AKT and MAPK activation and increased inhibitory phosphorylation of CHK1. Moreover, knockdown of wild-type HRAS or inhibition of CHK1 with AZD7762 sensitized KRAS-mutant cells to DNA-damaging agents. To address whether HRAS-mediated modulation of the DNA damage response facilitates mutant KRAS-driven carcinogenesis in vivo, HRAS was knocked down in established KRAS-mutant xenografts. Although HRAS depletion increased mitotic abnormalities, loss of wild-type HRAS alone did not alter KRAS-mutant tumor growth. However, HRAS depletion in the presence of the chemotherapeutic agent irinotecan led to significant, sustained tumor regression in association with ERK and AKT hyperactivation and inhibitory CHK1 phosphorylation. This work highlights a role for wild-type RAS-mediated regulation of the DNA damage response in KRAS-mutant driven tumorigenesis and points to the RAS–CHK1 axis as a potential vulnerability of KRAS-mutant cancers.
Grabocka E, Pylayeva-Gupta Y, Jones MJ, Lubkov V, Yemanaberhan E, Taylor L, et al. Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response. Cancer Cell 2014;25:243–56.
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