Ras-MEK Signaling Mediates a Critical Chk1-Dependent DNA Damage Response in Cancer Cells

Cancer cell line profiling to identify previously unrecognized kinase dependencies revealed a novel nonmutational dependency on the DNA damage response checkpoint kinase Chk1. Although Chk1 is a promising therapeutic target in p53-deficient cancers, we found that Ras-MEK signaling engages Chk1 in a subset of osteosarcoma, ovarian, and breast Cancer cells to enable their survival upon DNA damage, irrespective of p53 mutation status. Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes Cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Furthermore, exogenous DNA damage promotes Chk1 dependency, and pharmacologic Chk1 inhibition combined with genotoxic chemotherapy potentiates a DNA damage response and tumor cell killing. These findings reveal a mechanism-based diagnostic strategy to identify Cancer patients that may benefit from Chk1-targeted therapy. Mol Cancer Ther; 16(4); 694-704. ©2017 AACR.