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Ref Type Journal Article
PMID (33323455)
Authors Koivu MKA, Chakroborty D, Tamirat MZ, Johnson MS, Kurppa KJ, Elenius K
Title Identification of Predictive ERBB Mutations by Leveraging Publicly Available Cell Line Databases.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 20 3 2021 Mar 564-576 Mol Cancer Ther
URL
Abstract Text Although targeted therapies can be effective for a subgroup of patients, identification of individuals who benefit from the treatments is challenging. At the same time, the predictive significance of the majority of the thousands of mutations observed in the cancer tissues remains unknown. Here, we describe the identification of novel predictive biomarkers for ERBB-targeted tyrosine kinase inhibitors (TKIs) by leveraging the genetic and drug screening data available in the public cell line databases: Cancer Cell Line Encyclopedia, Genomics of Drug Sensitivity in Cancer, and Cancer Therapeutics Response Portal. We assessed the potential of 412 ERBB mutations in 296 cell lines to predict responses to 10 different ERBB-targeted TKIs. Seventy-six ERBB mutations were identified that were associated with ERBB TKI sensitivity comparable with non-small cell lung cancer cell lines harboring the well-established predictive EGFR L858R mutation or exon 19 deletions. Fourteen (18.4%) of these mutations were classified as oncogenic by the cBioPortal database, whereas 62 (81.6%) were regarded as novel potentially predictive mutations. Of the nine functionally validated novel mutations, EGFR Y1069C and ERBB2 E936K were transforming in Ba/F3 cells and demonstrated enhanced signaling activity. Mechanistically, the EGFR Y1069C mutation disrupted the binding of the ubiquitin ligase c-CBL to EGFR, whereas the ERBB2 E936K mutation selectively enhanced the activity of ERBB heterodimers. These findings indicate that integrating data from publicly available cell line databases can be used to identify novel, predictive nonhotspot mutations, potentially expanding the patient population benefiting from existing cancer therapies.

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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
ERBB3 E928fs frameshift loss of function - predicted ERBB3 (HER3) E928fs results in a change in the amino acid sequence of the Erbb3 (Her3) protein beginning at aa 928 of 1342, likely resulting in premature truncation of the functional protein (UniProt.org). E928fs (reported as E928fs*16) results in basal level Erbb3 (Her3) phosphorylation comparable to wild-type protein, but fails to transactivate coexpressed Erbb2 (Her2) in the presence of ligand, and is not transforming in culture (PMID: 33323455), and therefore, is predicted to lead to a loss of Erbb3 (Her3) protein function.
ERBB3 E952Q missense unknown ERBB3 (HER3) E952Q lies within the protein kinase domain of the Erbb3 (Her3) protein (UniProt.org). E952Q (reported as E933Q) results in increased ligand-dependent kinase activity in one study (PMID: 26378253), but demonstrates basal level phosphorylation comparable to wild-type protein, fails to transactivate coexpressed Erbb2 (Her2) in the presence of ligand, and is not transforming in culture (PMID: 33323455) and therefore, its effect on Erbb3 (Her3) protein function is unknown.
ERBB4 A17V missense no effect - predicted ERBB4 A17V lies within the signal peptide region of the Erbb4 protein (UniProt.org). A17V results in basal level and ligand-dependent phosphorylation of Erbb4 and downstream signaling comparable to wild-type protein, and is not transforming in culture (PMID: 33323455), and therefore, is predicted to have no effect on Erbb4 protein function.
ERBB4 G863E missense loss of function ERBB4 G863E lies within the protein kinase domain of the Erbb4 protein (UniProt.org). G863E a loss of ligand-dependent phosphorylation of Erbb4 and downstream signaling, reduced ability to promote ligand-dependent cell growth, and is not transforming in culture (PMID: 33323455).
ERBB4 G936R missense no effect ERBB4 G936R lies within the protein kinase domain of the Erbb4 protein (UniProt.org). G936R demonstrates Erbb4 phosphorylation comparable to wild-type Erbb4, and does not result in cell transformation in culture (PMID: 33323455).
ERBB4 L780P missense loss of function ERBB4 L780P lies within the protein kinase domain of the Erbb4 protein (UniProt.org). L780P results in a loss of ligand-dependent phosphorylation of Erbb4 and downstream signaling, reduced ability to promote ligand-dependent cell growth, and is not transforming in culture (PMID: 33323455).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB4 A17V hematologic cancer sensitive Erlotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ERBB4 A17V demonstrated sensitivity to Tarceva (erlotinib) similar to wild-type Erbb4 in culture, resulting in decreased cell viability (PMID: 33323455). 33323455
ERBB4 G936R Advanced Solid Tumor sensitive Erlotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ERBB4 G936R demonstrated sensitivity to Tarceva (erlotinib) similar to wild-type Erbb4 in culture, resulting in decreased cell viability (PMID: 33323455). 33323455
ERBB4 G936R Advanced Solid Tumor sensitive Afatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ERBB4 G936R demonstrated sensitivity to Gilotrif (afatinib) similar to wild-type Erbb2 in culture, resulting in decreased cell viability (PMID: 33323455). 33323455
ERBB4 G936R Advanced Solid Tumor sensitive Lapatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ERBB4 G936R demonstrated sensitivity to Tykerb (lapatinib) similar to wild-type Erbb4 in culture, resulting in decreased cell viability (PMID: 33323455). 33323455
ERBB4 G936R Advanced Solid Tumor sensitive Neratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ERBB4 G936R demonstrated sensitivity to Nerlynx (neratinib) similar to wild-type Erbb4 in culture, resulting in decreased cell viability (PMID: 33323455). 33323455
ERBB4 A17V hematologic cancer sensitive Neratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ERBB4 A17V demonstrated sensitivity to Nerlynx (neratinib) similar to wild-type Erbb4 in culture, resulting in decreased cell viability (PMID: 33323455). 33323455
ERBB4 A17V hematologic cancer sensitive Afatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ERBB4 A17V demonstrated sensitivity to Gilotrif (afatinib) similar to wild-type Erbb4 in culture, resulting in decreased cell viability (PMID: 33323455). 33323455
ERBB4 A17V hematologic cancer sensitive Lapatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ERBB4 A17V demonstrated sensitivity to Tykerb (lapatinib) similar to wild-type Erbb4 in culture, resulting in decreased cell viability (PMID: 33323455). 33323455