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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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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 |
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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 |