Wild-Type RAS: Keeping Mutant RAS in CHK

Anastassiadis, Theonie; Brown, Eric J.

doi:10.1016/j.ccr.2014.01.029

Cited by 1 publication

(1 citation statement)

References 11 publications

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“…In addition, Ras-MEK signaling engages ATR-Chk1 activation in various cancers to enable their survival upon chemotherapy-induced DNA damage ( 31 ). Expression of wild-type H- and N-RAS alters mutant RAS induced oncogenic signaling and DNA damage response, further affecting tumor progression and chemosensitivity ( 32 , 33 ). Despite these studies, there has been a lack of mechanistic understanding of how cytosolic, mutated KRAS promotes radioresistance, and whether this occurs through increased nuclear DNA repair activity or other mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic KRAS drives radioresistance through upregulation of NRF2-53BP1-mediated non-homologous end-joining repair

Yang

Shen

Estrada-Bernal

et al. 2021

Nucleic Acids Research

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KRAS-activating mutations are oncogenic drivers and are correlated with radioresistance of multiple cancers, including colorectal cancer, but the underlying precise molecular mechanisms remain elusive. Herein we model the radiosensitivity of isogenic HCT116 and SW48 colorectal cancer cell lines bearing wild-type or various mutant KRAS isoforms. We demonstrate that KRAS mutations indeed lead to radioresistance accompanied by reduced radiotherapy-induced mitotic catastrophe and an accelerated release from G2/M arrest. Moreover, KRAS mutations result in increased DNA damage response and upregulation of 53BP1 with associated increased non-homologous end-joining (NHEJ) repair. Remarkably, KRAS mutations lead to activation of NRF2 antioxidant signaling to increase 53BP1 gene transcription. Furthermore, genetic silencing or pharmacological inhibition of KRAS, NRF2 or 53BP1 attenuates KRAS mutation-induced radioresistance, especially in G1 phase cells. These findings reveal an important role for a KRAS-induced NRF2-53BP1 axis in the DNA repair and survival of KRAS-mutant tumor cells after radiotherapy, and indicate that targeting NRF2, 53BP1 or NHEJ may represent novel strategies to selectively abrogate KRAS mutation-mediated radioresistance.

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Section: Introductionmentioning

confidence: 99%