Reference Detail

Ref Type

Journal Article

PMID

(38751013)

Authors

Mishra R, Kilroy MK, Feroz W, Patel H, Garrett JT

Title

HER3 V104 mutations regulate cell signaling, growth, and drug sensitivity in cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular carcinogenesis			2024 May 15		Mol Carcinog

URL

Abstract Text

HER3 is mutated in ~2%-10% of cancers depending on the cancer type. We found the HER3-V104L mutation to be activating from patient-derived mutations introduced via lentiviral transduction in HER3KO HER2 + HCC1569 breast cancer cells in which endogenous HER3 was eliminated by CRISPR/Cas9. Cells expressing HER3-V104L showed higher p-HER3 and p-ERK1/2 expression versus cells expressing wild-type HER3 or HER3-V104M. Patients whose tumor expressed the HER3 V104L variant had a reduced probability of overall survival compared to patients lacking a HER3 mutation whereas we did not find a statistically significant difference in overall survival of various cancer patients with the HER3 V104M mutation. Our data showed that HER2 inhibitors suppressed cell growth of HCC1569HER3KO cells stably expressing the HER3-V104L mutation. Cancer cell lines (SNU407, UC15 and DV90) with endogenous HER3-V104M mutation showed reduced cell proliferation and p-HER2/p-ERK1/2 expression with HER2 inhibitor treatment. Knock down of HER3 abrogated cell proliferation in the above cell lines which were overall more sensitive to the ERK inhibitor SCH779284 versus PI3K inhibitors. HER3-V104L mutation stabilized HER3 protein expression in COS7 and SNUC5 cells. COS7 cells transiently transfected with the HER3-V104L mutation in the presence of HER binding partners showed higher expression of p-HER3, p-ERK1/2 versus HER3-WT in a NRG-independent manner without any change in AKT signaling. Overall, this study shows the clinical relevance of the HER3 V104L and the V104M mutations and its response to HER2, PI3K and ERK inhibitors.

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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	V104L	missense	gain of function	ERBB3 (HER3) V104L lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org). V104L confers a gain of function to the Erbb3 (Her3) protein as demonstrated by increased phosphorylation of Erbb3 (Her3) and downstream signaling (PMID: 24909266, PMID: 38751013), increased colony formation, migration (PMID: 29954840), and proliferation in culture (PMID: 29954840, PMID: 38751013), and enhanced tumor growth in mouse models (PMID: 29954840).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ERBB3 V104M	urinary bladder cancer	sensitive	Alpelisib	Preclinical - Cell culture	Actionable	In a preclinical study, Piqray (alpelisib) treatment inhibited proliferation of a bladder cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	lung cancer	sensitive	Tucatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tukysa (tucatinib) treatment inhibited Erbb2 (Her2) phosphorylation and downstream signaling, and inhibited viability, proliferation, and colony formation in a lung cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	colon cancer	sensitive	Buparlisib	Preclinical - Cell culture	Actionable	In a preclinical study, Buparlisib (BKM120) treatment inhibited proliferation of a colon cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	colon cancer	sensitive	Tucatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tukysa (tucatinib) treatment inhibited Erbb2 (Her2) phosphorylation and downstream signaling, and inhibited growth in a colon cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	urinary bladder cancer	sensitive	SCH772984	Preclinical - Cell culture	Actionable	In a preclinical study, SCH772984 treatment inhibited proliferation of a bladder cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	colon cancer	sensitive	Alpelisib	Preclinical - Cell culture	Actionable	In a preclinical study, Piqray (alpelisib) treatment inhibited proliferation of a colon cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	colon cancer	sensitive	SCH772984	Preclinical - Cell culture	Actionable	In a preclinical study, SCH772984 treatment inhibited proliferation of a colon cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104L	Her2-receptor positive breast cancer	sensitive	Tucatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tukysa (tucatinib) treatment inhibited activation of Erbb2 (Her2) and decreased viability and proliferation in an ERBB2 (HER2)-positive breast cancer cell line expressing ERBB3 (HER3) V104L in culture (PMID: 38751013).	38751013
ERBB3 V104M	lung cancer	sensitive	Alpelisib	Preclinical - Cell culture	Actionable	In a preclinical study, Piqray (alpelisib) treatment inhibited proliferation of a lung cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	urinary bladder cancer	sensitive	Buparlisib	Preclinical - Cell culture	Actionable	In a preclinical study, Buparlisib (BKM120) treatment inhibited proliferation of a bladder cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	colon cancer	sensitive	Neratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Nerlynx (neratinib) treatment inhibited Erbb2 (Her2) phosphorylation and downstream signaling, and inhibited viability and proliferation in a colon cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	lung cancer	sensitive	SCH772984	Preclinical - Cell culture	Actionable	In a preclinical study, SCH772984 treatment inhibited proliferation of a lung cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	lung cancer	sensitive	Neratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Nerlynx (neratinib) treatment inhibited Erbb2 (Her2) phosphorylation and downstream signaling, and inhibited viability and colony formation in a lung cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	lung cancer	sensitive	Buparlisib	Preclinical - Cell culture	Actionable	In a preclinical study, Buparlisib (BKM120) treatment inhibited proliferation of a lung cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	urinary bladder cancer	sensitive	Tucatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tukysa (tucatinib) treatment inhibited Erbb2 (Her2) phosphorylation and downstream signaling, and inhibited growth in a bladder cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104M	urinary bladder cancer	sensitive	Neratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Nerlynx (neratinib) treatment inhibited Erbb2 (Her2) phosphorylation and downstream signaling, and inhibited viability and proliferation in a bladder cancer cell line harboring ERBB3 (HER3) V104M in culture (PMID: 38751013).	38751013
ERBB3 V104L	Her2-receptor positive breast cancer	sensitive	Neratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Nerlynx (neratinib) treatment inhibited activation of Erbb2 (Her2) and decreased viability and proliferation in an ERBB2 (HER2)-positive breast cancer cell line expressing ERBB3 (HER3) V104L in culture (PMID: 38751013).	38751013
ERBB3 V104L	Her2-receptor positive breast cancer	sensitive	Afatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Gilotrif (afatinib) treatment inhibited activation of Erbb2 (Her2) and decreased viability and proliferation in an ERBB2 (HER2)-positive breast cancer cell line expressing ERBB3 (HER3) V104L in culture (PMID: 38751013).	38751013