Reference Detail

Ref Type Journal Article
PMID (23934108)
Authors Hatzivassiliou G, Haling JR, Chen H, Song K, Price S, Heald R, Hewitt JF, Zak M, Peck A, Orr C, Merchant M, Hoeflich KP, Chan J, Luoh SM, Anderson DJ, Ludlam MJ, Wiesmann C, Ultsch M, Friedman LS, Malek S, Belvin M
Title Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers.
Journal Nature
Vol 501
Issue 7466
Date 2013 Sep 12
URL
Abstract Text KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. Conversely, potent inhibition of active, phosphorylated MEK is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in superior efficacy in this genotype with GDC-0973 (also known as cobimetinib), a MEK inhibitor currently in phase III clinical trials. Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK. These inhibitors are currently being evaluated in clinical trials to determine whether improvements in therapeutic index within KRAS versus BRAF preclinical models translate to improved clinical responses in patients.

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Molecular Profile Treatment Approach
KRAS Q61H MEK inhibitor (Pan)
KRAS G12W MEK1 Inhibitor
KRAS K147E MEK inhibitor (Pan)
KRAS P34L MEK2 Inhibitor
KRAS K147E MEK2 Inhibitor
KRAS G12S MEK inhibitor (Pan)
KRAS G12I MEK inhibitor (Pan)
KRAS A146T MEK1 Inhibitor
KRAS Q61K MEK inhibitor (Pan)
KRAS V14L MEK1 Inhibitor
KRAS G12W MEK inhibitor (Pan)
KRAS Y32S MEK2 Inhibitor
KRAS G12N MEK inhibitor (Pan)
KRAS K117N MEK inhibitor (Pan)
KRAS Q61E MEK1 Inhibitor
KRAS G12A MEK1 Inhibitor
KRAS G12C MEK1 Inhibitor
KRAS G10dup MEK2 Inhibitor
KRAS N116S MEK inhibitor (Pan)
KRAS A146V MEK1 Inhibitor
KRAS Q61K MEK1 Inhibitor
KRAS G12D MEK1 Inhibitor
KRAS Q61A MEK inhibitor (Pan)
KRAS N116S MEK2 Inhibitor
KRAS D33E MEK1 Inhibitor
KRAS C118S MEK2 Inhibitor
KRAS L19F MEK inhibitor (Pan)
KRAS T58I MEK2 Inhibitor
KRAS E63K MEK1 Inhibitor
KRAS T74P MEK1 Inhibitor
KRAS G10dup MEK1 Inhibitor
KRAS P34R MEK1 Inhibitor
KRAS L19F MEK1 Inhibitor
KRAS T74P MEK2 Inhibitor
KRAS F156L MEK2 Inhibitor
KRAS G12Y MEK inhibitor (Pan)
KRAS G13D MEK2 Inhibitor
KRAS Y40A MEK2 Inhibitor
KRAS D33E MEK inhibitor (Pan)
KRAS A11_G12insGA MEK1 Inhibitor
KRAS C118S MEK1 Inhibitor
KRAS F28L MEK inhibitor (Pan)
KRAS Q61H MEK2 Inhibitor
KRAS G12F MEK1 Inhibitor
KRAS Q22E MEK inhibitor (Pan)
KRAS D153V MEK inhibitor (Pan)
KRAS F156L MEK1 Inhibitor
KRAS D153V MEK1 Inhibitor
KRAS Q61P MEK inhibitor (Pan)
KRAS A146T MEK2 Inhibitor
KRAS G12R MEK inhibitor (Pan)
KRAS E63K MEK2 Inhibitor
KRAS G12Y MEK1 Inhibitor
KRAS V14I MEK inhibitor (Pan)
KRAS G12E MEK1 Inhibitor
KRAS G12E MEK2 Inhibitor
KRAS G13X MEK1 Inhibitor
KRAS Q61R MEK1 Inhibitor
KRAS V14L MEK2 Inhibitor
KRAS D33E MEK2 Inhibitor
KRAS C118S MEK inhibitor (Pan)
KRAS G12L MEK1 Inhibitor
KRAS G12S MEK2 Inhibitor
KRAS G12V MEK2 Inhibitor
KRAS G12X MEK2 Inhibitor
KRAS Q22K MEK2 Inhibitor
KRAS G12E MEK inhibitor (Pan)
KRAS Q61X MEK inhibitor (Pan)
KRAS P34L MEK1 Inhibitor
KRAS P34R MEK2 Inhibitor
KRAS G13X MEK2 Inhibitor
KRAS T58I MEK1 Inhibitor
KRAS G12V MEK inhibitor (Pan)
KRAS Q61L MEK2 Inhibitor
KRAS G12R MEK1 Inhibitor
KRAS G13X MEK inhibitor (Pan)
KRAS G60R MEK2 Inhibitor
KRAS Q61E MEK2 Inhibitor
KRAS Q22E MEK2 Inhibitor
KRAS G12A MEK2 Inhibitor
KRAS G10dup MEK inhibitor (Pan)
KRAS G12A MEK inhibitor (Pan)
KRAS D153V MEK2 Inhibitor
KRAS Q22R MEK2 Inhibitor
KRAS Q61L MEK1 Inhibitor
KRAS Q22E MEK1 Inhibitor
KRAS T58I MEK inhibitor (Pan)
KRAS A146T MEK inhibitor (Pan)
KRAS G12V MEK1 Inhibitor
KRAS V14I MEK1 Inhibitor
KRAS F28L MEK2 Inhibitor
KRAS N116H MEK inhibitor (Pan)
KRAS Q61E MEK inhibitor (Pan)
KRAS N116H MEK2 Inhibitor
KRAS G13D MEK inhibitor (Pan)
KRAS Q22R MEK1 Inhibitor
KRAS Q61R MEK inhibitor (Pan)
KRAS Q22K MEK inhibitor (Pan)
KRAS E62K MEK1 Inhibitor
KRAS G12Y MEK2 Inhibitor
KRAS P34R MEK inhibitor (Pan)
KRAS L19F MEK2 Inhibitor
KRAS A146V MEK2 Inhibitor
KRAS Q61X MEK2 Inhibitor
KRAS G12N MEK1 Inhibitor
KRAS G12I MEK2 Inhibitor
KRAS Y71H MEK1 Inhibitor
KRAS E62K MEK inhibitor (Pan)
KRAS G12D MEK2 Inhibitor
KRAS G13C MEK inhibitor (Pan)
KRAS G12W MEK2 Inhibitor
KRAS Y71H MEK2 Inhibitor
KRAS Q22R MEK inhibitor (Pan)
KRAS A59G MEK inhibitor (Pan)
KRAS N116S MEK1 Inhibitor
KRAS G13D MEK1 Inhibitor
KRAS F28L MEK1 Inhibitor
KRAS Q61L MEK inhibitor (Pan)
KRAS Q61H MEK1 Inhibitor
KRAS K5N MEK1 Inhibitor
KRAS Q61R MEK2 Inhibitor
KRAS Y40A MEK inhibitor (Pan)
KRAS Q22K MEK1 Inhibitor
KRAS V14I MEK2 Inhibitor
KRAS K5N MEK2 Inhibitor
KRAS K117N MEK2 Inhibitor
KRAS N116H MEK1 Inhibitor
KRAS A11_G12insGA MEK2 Inhibitor
KRAS G12R MEK2 Inhibitor
KRAS A11_G12insGA MEK inhibitor (Pan)
KRAS A59G MEK1 Inhibitor
KRAS Q61X MEK1 Inhibitor
KRAS V14L MEK inhibitor (Pan)
KRAS G13C MEK2 Inhibitor
KRAS G12N MEK2 Inhibitor
KRAS A59G MEK2 Inhibitor
KRAS Y32S MEK inhibitor (Pan)
KRAS G12X MEK1 Inhibitor
KRAS Y40A MEK1 Inhibitor
KRAS G60R MEK1 Inhibitor
KRAS G12L MEK2 Inhibitor
KRAS Q61P MEK1 Inhibitor
KRAS E63K MEK inhibitor (Pan)
KRAS T74P MEK inhibitor (Pan)
KRAS G12F MEK inhibitor (Pan)
KRAS G12C MEK inhibitor (Pan)
KRAS F156L MEK inhibitor (Pan)
KRAS G12C MEK2 Inhibitor
KRAS E62K MEK2 Inhibitor
KRAS G12L MEK inhibitor (Pan)
KRAS Y32S MEK1 Inhibitor
KRAS G12I MEK1 Inhibitor
KRAS P34L MEK inhibitor (Pan)
KRAS Q61K MEK2 Inhibitor
KRAS K5N MEK inhibitor (Pan)
KRAS G12F MEK2 Inhibitor
KRAS G12X MEK inhibitor (Pan)
KRAS G12D MEK inhibitor (Pan)
KRAS Q61A MEK2 Inhibitor
KRAS G13C MEK1 Inhibitor
KRAS K117N MEK1 Inhibitor
KRAS Q61P MEK2 Inhibitor
KRAS Q61A MEK1 Inhibitor
KRAS A146V MEK inhibitor (Pan)
KRAS G12S MEK1 Inhibitor
KRAS K147E MEK1 Inhibitor
KRAS G60R MEK inhibitor (Pan)
KRAS Y71H MEK inhibitor (Pan)
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
GDC-0623 GDC-0623 5 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
GDC-0623 MEK inhibitor (Pan) 20 GDC-0623 is a Mek1/2 inhibitor, which results in inhibition of growth factor-mediated signaling and tumor cell proliferation (PMID: 23934108, PMID: 26615130).
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
KRAS G12X non-small cell lung carcinoma sensitive Cobimetinib Preclinical - Cell line xenograft Actionable In a preclinical study, Cobimetinib (GDC-0973) inhibited tumor growth in xenograft models of a human non-small cell lung cancer cell line harboring a KRAS codon 12 mutation (PMID: 23934108). 23934108
KRAS G12X pancreatic cancer sensitive Cobimetinib Preclinical - Cell line xenograft Actionable In a preclinical study, Cobimetinib (GDC-0973) inhibited tumor growth in xenograft models of a human pancreatic cancer cell line harboring a KRAS codon 12 mutation (PMID: 23934108). 23934108
KRAS G12C pancreatic cancer sensitive GDC-0623 Preclinical - Cell line xenograft Actionable In a preclinical study, GDC-0623 induced tumor regression in pancreatic cancer cell line xenograft models harboring KRAS G12C (PMID: 23934108). 23934108
KRAS G13D Advanced Solid Tumor sensitive GDC-0623 Preclinical - Cell line xenograft Actionable In a preclinical study, GDC-0623 demonstrated efficacy against both KRAS-mutant and BRAF-mutant cancer models in cell based assays and cell line xenografts (PMID: 23934108). 23934108
KRAS mutant Advanced Solid Tumor sensitive GDC-0623 Preclinical - Cell line xenograft Actionable In a preclinical study, GDC-0623 demonstrated efficacy in several human tumor cell line xenograft models harboring KRAS mutations (PMID: 23934108). 23934108
KRAS G13D colorectal cancer sensitive Cobimetinib Preclinical - Cell line xenograft Actionable In a preclinical study, Cobimetinib (GDC-0973) inhibited tumor growth in xenograft models of human colorectal cancer cell lines harboring KRAS G13D (PMID: 23934108). 23934108
KRAS G12C pancreatic cancer sensitive Cobimetinib Preclinical - Cell line xenograft Actionable In a preclinical study, Cobimetinib (GDC-0973) inhibited tumor growth in xenograft models of a human pancreatic cancer cell line harboring KRAS G12C (PMID: 23934108). 23934108
KRAS G12C non-small cell lung carcinoma sensitive Cobimetinib Preclinical - Cell line xenograft Actionable In a preclinical study, Cobimetinib (GDC-0973) inhibited tumor growth in xenograft models of a human non-small cell lung cancer cell line harboring KRAS G12C (PMID: 23934108). 23934108