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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 F94L missense unknown ERBB3 (HER3) F94L lies within the extracellular domain of the Erbb3 (Her3) protein (PMID: 29963236). The functional effect of F94L is conflicting as it does not result in increased cell proliferation relative to wild-type Erbb3 (Her3) in ER-positive breast cancer cells (PMID: 29963236) and does not lead to increased downstream signaling or cell proliferation in Erbb2 (Her2)-positive breast cancer cells in culture (PMID: 38751013), but in another study results in elevated cell proliferation in Erbb2 (Her2)-overexpressing cells in culture (PMID: 29963236), and therefore, its effect on Erbb3 (Her3) protein function is unknown.
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).
ERBB3 V104M missense unknown ERBB3 (HER3) V104M lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org). V104M results in increased viability (PMID: 38751013), phosphorylation of Akt and Erk, and transformation in Erbb2 (Her2)-expressing cells in culture (PMID: 23680147), however, demonstrates cell proliferation and viability (PMID: 29533785) in the context of endogenous Erbb2 (Her2), and viability and downstream signaling in cells expressing ERBB2 (HER2) V956R (PMID: 38806620) similar to wild-type Erbb3 (Her3) in culture, and therefore, its effect on Erbb3 (Her3) protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 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 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 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 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
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 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 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 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 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 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 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 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 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 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