Reference Detail

Ref Type

Journal Article

PMID

(28145866)

Authors

Krall EB, Wang B, Munoz DM, Ilic N, Raghavan S, Niederst MJ, Yu K, Ruddy DA, Aguirre AJ, Kim JW, Redig AJ, Gainor JF, Williams JA, Asara JM, Doench JG, Janne PA, Shaw AT, McDonald Iii RE, Engelman JA, Stegmeier F, Schlabach MR, Hahn WC

Title

KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
eLife	6		2017 Feb 01		Elife

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E KEAP1 loss	lung cancer	decreased response	Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, KEAP1 knockout resulted in decreased sensitivity to Zelboraf (vemurafenib) in a lung cancer cell line harboring BRAF V600E in culture (PMID: 28145866).	28145866
KEAP1 loss NRAS Q61K	lung cancer	decreased response	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, KEAP1 knockout resulted in decreased sensitivity to Mekinist (trametinib) in a lung cancer cell line harboring NRAS Q61K in culture (PMID: 28145866).	28145866
BRAF V600E KEAP1 loss	lung cancer	decreased response	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, KEAP1 knockout resulted in decreased sensitivity to Mekinist (trametinib) in a lung cancer cell line harboring BRAF V600E in culture (PMID: 28145866).	28145866
EML4 - ALK KEAP1 dec exp	lung cancer	sensitive	Crizotinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, KEAP1 knockout resulted in decreased sensitivity to Xalkori (crizotinib) in a lung cancer cell line and patient-derived lung cancer cells harboring EML4-ALK in culture (PMID: 28145866).	28145866
EML4 - ALK KEAP1 dec exp	lung cancer	decreased response	Ceritinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, KEAP1 knockout resulted in decreased sensitivity to Zykadia (ceritinib) in patient-derived lung cancer cells harboring EML4-ALK in culture (PMID: 28145866).	28145866