TY - JOUR TI - KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer AU - Krall, Elsa B AU - Wang, Belinda AU - Munoz, Diana M AU - Ilic, Nina AU - Raghavan, Srivatsan AU - Niederst, Matthew J AU - Yu, Kristine AU - Ruddy, David A AU - Aguirre, Andrew J AU - Kim, Jong Wook AU - Redig, Amanda J AU - Gainor, Justin F AU - Williams, Juliet A AU - Asara, John M AU - Doench, John G AU - Janne, Pasi A AU - Shaw, Alice T AU - McDonald III, Robert E AU - Engelman, Jeffrey A AU - Stegmeier, Frank AU - Schlabach, Michael R AU - Hahn, William C A2 - McMahon, Martin VL - 6 PY - 2017 DA - 2017/02/01 SP - e18970 C1 - eLife 2017;6:e18970 DO - 10.7554/eLife.18970 UR - https://doi.org/10.7554/eLife.18970 AB - Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of KEAP1, a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway. KW - CRISPR-Cas9 KW - drug resistance KW - lung cancer JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -