Oncogenic Alterations in <i>ERBB2/HER2</i> Represent Potential Therapeutic Targets Across Tumors From Diverse Anatomic Sites of Origin

Chmielecki, Juliann; Ross, Jeffrey S.; Wang, Kai; Frampton, Garrett M.; Palmer, Gary A.; Ali, Siraj M.; Palma, Norma Alonzo; Morosini, Deborah; Miller, Vincent A.; Yelensky, Roman; Lipson, Doron; Stephens, Philip J.

doi:10.1634/theoncologist.2014-0234

Cited by 78 publications

(67 citation statements)

References 49 publications

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“…Genomic profiling of human cancers has identified recurrent somatic mutations of HER2 ( ERBB2 ) and HER3 ( ERBB3 ), typically occurring in the absence of gene amplification 1–3 . Mutations in HER2 are clustered in the extracellular, transmembrane, and kinase domains.…”

Section: Introductionmentioning

confidence: 99%

HER kinase inhibition in patients with HER2- and HER3-mutant cancers

Hyman

Piha-Paul

Won

et al. 2018

Nature

630

545

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Summary Somatic mutations of ERBB2 (HER2) and ERBB3 (HER3) are found in a wide range of cancers. Preclinical modelling suggests that a subset lead to constitutive HER2 activation, but most remain biologically uncharacterized. We sought to prospectively define the biologic and therapeutic significance of known oncogenic HER2 and HER3 mutations and variants of unknown biological significance by conducting a multi-histology, genomically selected, ‘basket’ study utilizing the pan-HER kinase inhibitor neratinib (SUMMIT; Clinicaltrials.gov 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 harbouring kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to further refine our biological understanding of both characterized and novel genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.

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Section: Introductionmentioning

confidence: 99%

HER kinase inhibition in patients with HER2- and HER3-mutant cancers

Hyman

Piha-Paul

Won

et al. 2018

Nature

630

545

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“…Recent publications have suggested a broad spectrum of genomic changes in clinically relevant targets (29,(36)(37)(38), and expanded analyses are warranted to identify more patients predicted to be sensitive or resistant to targeted therapies. Furthermore, the identification of drug sensitivity and resistance biomarkers across multiple indications suggests that targeted agents may have broader utility beyond that for which they were approved originally.…”

Section: Spectrum Of Known Clinically Relevant Alterations Across Dismentioning

confidence: 99%

High-Throughput Genomic Profiling of Adult Solid Tumors Reveals Novel Insights into Cancer Pathogenesis

Hartmaier¹,

Albacker²,

Chmielecki³

et al. 2017

Cancer Research

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107

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Genomic profiling is widely predicted to become a standard of care in clinical oncology, but more effective data sharing to accelerate progress in precision medicine will be required. Here, we describe cancer-associated genomic profiles from 18,004 unique adult cancers. The dataset was composed of 162 tumor subtypes including multiple rare and uncommon tumors. Comparison of alteration frequencies to The Cancer Genome Atlas identified some differences and suggested an enrichment of treatment-refractory samples in breast and lung cancer cohorts. To illustrate novelty within the dataset, we surveyed the genomic landscape of rare diseases and identified an increased frequency of NOTCH1 alterations in adenoid cystic carcinomas compared with previous studies. Analysis of tumor suppressor gene patterns revealed disease specificity for certain genes but broad inactivation of others. We identified multiple potentially druggable, novel and known kinase fusions in diseases beyond those in which they are currently recognized. Analysis of variants of unknown significance identified an enrichment of SMAD4 alterations in colon cancer and other rare alterations predicted to have functional impact. Analysis of established, clinically relevant alterations highlighted the spectrum of molecular changes for which testing is currently recommended, as well as opportunities for expansion of indications for use of approved targeted therapies. Overall, this dataset presents a new resource with which to investigate rare alterations and diseases, validate clinical relevance, and identify novel therapeutic targets. Cancer Res; 77(9); 2464–75. ©2017 AACR.

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“…DNA sequencing efforts have revealed that ERBB2 , the gene encoding the HER2 receptor tyrosine kinase (RTK), is mutated a wide variety of cancer types, including 2–3% of primary breast cancers (1–3), with a higher incidence in lobular breast cancers (4). More than 70% of HER2 mutations in breast cancer are found in the absence of HER2 ( ERBB2 ) gene amplification (2).…”

Section: Introductionmentioning

confidence: 99%

An Acquired HER2 T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant–Driven Breast Cancer

et al. 2017

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We report a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2L869R but not HER2L869R/T798I. In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2L869R/T798I-induced signaling and cell growth. Acquisition of HER2T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2L869R is a driver mutation. HER2T798I-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib.

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Oncogenic Alterations in ERBB2/HER2 Represent Potential Therapeutic Targets Across Tumors From Diverse Anatomic Sites of Origin

Cited by 78 publications

References 49 publications

HER kinase inhibition in patients with HER2- and HER3-mutant cancers

HER kinase inhibition in patients with HER2- and HER3-mutant cancers

High-Throughput Genomic Profiling of Adult Solid Tumors Reveals Novel Insights into Cancer Pathogenesis

An Acquired HER2 T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant–Driven Breast Cancer

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