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Ref Type Journal Article
PMID (29420467)
Authors Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, Juric D, Quinn DI, Moreno V, Doger B, Mayer IA, Boni V, Calvo E, Loi S, Lockhart AC, Erinjeri JP, Scaltriti M, Ulaner GA, Patel J, Tang J, Beer H, Selcuklu SD, Hanrahan AJ, Bouvier N, Melcer M, Murali R, Schram AM, Smyth LM, Jhaveri K, Li BT, Drilon A, Harding JJ, Iyer G, Taylor BS, Berger MF, Cutler RE, Xu F, Butturini A, Eli LD, Mann G, Farrell C, Lalani AS, Bryce RP, Arteaga CL, Meric-Bernstam F, Baselga J, Solit DB
Title HER kinase inhibition in patients with HER2- and HER3-mutant cancers.
Journal Nature
Vol 554
Issue 7691
Date 2018 Feb 08
URL
Abstract Text Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.

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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
ATR R1183Q missense unknown ATR R1183Q does not lie within any known functional domains of the Atr protein (UniProt.org). R1183Q has been identified in sequencing studies (PMID: 29420467), but has not been biochemically characterized and therefore, its effect on Atr protein function is unknown (PubMed, Nov 2020).
CDK12 R1008Q missense unknown CDK12 R1008Q lies within the protein kinase domain of the Cdk12 protein (PMID: 22512864). R1008Q has been identified in sequencing studies (PMID: 29420467), but has not been biochemically characterized and therefore, its effect on Cdk12 protein function is unknown (PubMed, Mar 2021).
FANCA V580M missense unknown FANCA V580M does not lie within any known functional domains of the Fanca protein (UniProt.org). V580M has been identified in sequencing studies (PMID: 29420467), but has not been biochemically characterized and therefore, its effect on Fanca protein function is unknown (PubMed, Jan 2021).
JAK2 R487C missense unknown JAK2 R487C does not lie within any known functional domains of the Jak2 protein (UniProt.org). R487C has been identified in sequencing studies (PMID: 29420467, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Apr 2021).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References