Reference Detail

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			2020 Dec 15	564-576	Mol Cancer Ther

URL

Abstract Text

While 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 vast 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 (TKI) by leveraging the genetic and drug screening data available in the public cell line databases: Cancer Cell Line Encyclopedia (CCLE), Genomics of Drug Sensitivity in Cancer (GDSC), and Cancer Therapeutics Response Portal (CTRP). 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 to 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. Out of 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 non-hotspot 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
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	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 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 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	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 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	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 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	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