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Ref Type Journal Article
PMID (23680147)
Authors Jaiswal BS, Kljavin NM, Stawiski EW, Chan E, Parikh C, Durinck S, Chaudhuri S, Pujara K, Guillory J, Edgar KA, Janakiraman V, Scholz RP, Bowman KK, Lorenzo M, Li H, Wu J, Yuan W, Peters BA, Kan Z, Stinson J, Mak M, Modrusan Z, Eigenbrot C, Firestein R, Stern HM, Rajalingam K, Schaefer G, Merchant MA, Sliwkowski MX, de Sauvage FJ, Seshagiri S
Title Oncogenic ERBB3 mutations in human cancers.
Journal Cancer cell
Vol 23
Issue 5
Date 2013 May 13
URL
Abstract Text The human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ~11% of colon and gastric cancers. We found that the ERBB3 mutants transformed colonic and breast epithelial cells in a ligand-independent manner. However, the mutant ERBB3 oncogenic activity was dependent on kinase-active ERBB2. Furthermore, we found that anti-ERBB antibodies and small molecule inhibitors effectively blocked mutant ERBB3-mediated oncogenic signaling and disease progression in vivo.

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Molecular Profile Treatment Approach
ERBB3 Q809R HER2 Inhibitor
ERBB3 act mut HER2 Inhibitor
ERBB3 E928G HER2 Inhibitor
ERBB3 P262H HER inhibitor (Pan)
ERBB3 P262H Pertuzumab
ERBB3 over exp HER3 Inhibitor
ERBB3 A232V HER2 Inhibitor
ERBB3 V104L HER3 Inhibitor
ERBB3 act mut Pertuzumab
ERBB3 E928G HER3 Inhibitor
ERBB3 Q809R HER3 Inhibitor
ERBB3 S846I HER inhibitor (Pan)
ERBB3 over exp HER3 (ERBB3) Antibody
ERBB3 V855A HER3 Inhibitor
ERBB3 amp HER3 (ERBB3) Antibody
ERBB3 V104L Trastuzumab
ERBB3 amp HER2 Inhibitor
ERBB3 amp HER3 Inhibitor
ERBB3 Q809R Pertuzumab
ERBB3 T389K Pertuzumab
ERBB3 P262H HER3 Inhibitor
ERBB3 S846I Pertuzumab
ERBB3 over exp HER2 (ERBB2) Vaccine
ERBB3 T355I HER inhibitor (Pan)
ERBB3 T355I HER2 Inhibitor
ERBB3 Q809R Trastuzumab
ERBB3 amp HER inhibitor (Pan)
ERBB3 V855A HER inhibitor (Pan)
ERBB3 A232V HER inhibitor (Pan)
ERBB3 V104L HER2 Inhibitor
ERBB3 V104L HER inhibitor (Pan)
ERBB3 Q809R HER inhibitor (Pan)
ERBB3 S846I HER2 Inhibitor
ERBB3 V104L Pertuzumab
ERBB3 over exp HER2 (ERBB2) Antibody
ERBB3 E928G Trastuzumab
ERBB3 act mut HER inhibitor (Pan)
ERBB3 act mut HER3 Inhibitor
ERBB3 P262H HER2 Inhibitor
ERBB3 P262H Trastuzumab
ERBB3 amp HER2 (ERBB2) Vaccine
ERBB3 amp HER2 (ERBB2) Antibody
ERBB3 A232V Pertuzumab
ERBB3 T355I HER3 Inhibitor
ERBB3 A232V Trastuzumab
ERBB3 V855A HER2 Inhibitor
ERBB3 T389K HER inhibitor (Pan)
ERBB3 A232V HER3 Inhibitor
ERBB3 T389K HER3 Inhibitor
ERBB3 T389K HER2 Inhibitor
ERBB3 T389K Trastuzumab
ERBB3 over exp HER2 Inhibitor
ERBB3 over exp HER inhibitor (Pan)
ERBB3 S846I HER3 Inhibitor
ERBB3 act mut Trastuzumab
ERBB3 E928G Pertuzumab
ERBB3 E928G HER inhibitor (Pan)
ERBB3 S846I Trastuzumab
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 A232V missense gain of function ERBB3 (HER3) A232V lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org, PMID: 23680147). A232V confers a gain of Erbb3 (Her3) protein function, resulting in phosphorylation of Akt and Erk, as well as oncogenic transformation of Erbb2 (Her2) expressing cells (PMID: 23680147).
ERBB3 E928G missense gain of function ERBB3 (HER3) E928G lies within the protein kinase domain of the Erbb3 (Her3) protein (UniProt.org). E928G confers a gain of Erbb3 (Her3) protein function, resulting in phosphorylation of Akt and Erk, as well as oncogenic transformation of Erbb2 (Her2) expressing cells (PMID: 23680147).
ERBB3 G284R missense unknown ERBB3 (HER3) G284R lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org). G284R results in increased phosphorylation of Akt and Erk, as well as oncogenic transformation of Erbb2 (Her2) expressing cells relative to wild-type Erbb3 (Her3) (PMID: 23680147) and leads to increased cell proliferation in Erbb2 (Her2)-overexpressing cells in culture (PMID: 29963236), but has not been individually characterized and therefore, its effect on Erbb3 (Her3) protein function is unknown.
ERBB3 P262H missense gain of function ERBB3 (HER3) P262H lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org). P262H confers a gain of Erbb3 (Her3) protein function, resulting in phosphorylation of Akt and Erk, as well as oncogenic transformation of Erbb2 (Her2) expressing cells (PMID: 23680147).
ERBB3 Q809R missense gain of function ERBB3 (HER3) Q809R lies within the protein kinase domain of the Erbb3 (Her3) protein (UniProt.org). Q809R confers a gain of Erbb3 (Her3) protein function, resulting in phosphorylation of Akt and Erk, as well as oncogenic transformation of Erbb2 (Her2) expressing cells (PMID: 23680147).
ERBB3 S846I missense gain of function ERBB3 (HER3) S846I lies within the protein kinase domain of the Erbb3 (Her3) protein (UniProt.org). S846I confers a gain of Erbb3 (Her3) protein function, resulting in phosphorylation of Akt and Erk, as well as oncogenic transformation of Erbb2 (Her2) expressing cells (PMID: 23680147).
ERBB3 T389K missense gain of function ERBB3 (HER3) T389K lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org). T389K confers a gain of Erbb3 (Her3) protein function, resulting in phosphorylation of Akt and Erk, as well as oncogenic transformation of Erbb2 (Her2) expressing cells (PMID: 23680147).
ERBB3 V104M missense unknown ERBB3 (HER3) V104M lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org). V104M results in phosphorylation of Akt and Erk, and transformation of Erbb2 (Her2)-expressing cells in culture (PMID: 23680147), however, V104M results in similar cell proliferation and viability levels as wild-type Erbb3 (Her3) in another study (PMID: 29533785), and therefore, its effect on Erbb3 (Her3) protein function is unknown.
ERBB3 V714M missense no effect ERBB3 (HER3) V714M lies within the protein kinase domain of the Erbb3 (Her3) protein (UniProt.org). V714M demonstrates growth promotion and transforming ability in the presence of Erbb2 (Her2) similar to wild-type Erbb3 (Her3) in culture (PMID: 23680147).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB3 Q809R Advanced Solid Tumor resistant Cetuximab Preclinical Actionable In a preclinical study, transformed cell lines expressing ERBB3 (HER3) Q809R demonstrated resistance to treatment with Erbitux (cetuximab) (PMID: 23680147). 23680147
ERBB3 P262H Advanced Solid Tumor sensitive PD-0325901 + Pictilisib Preclinical Actionable In a preclinical study, the combination of GDC-0941 and PD-0325901 (PI3K and MEK inhibitors, respectively) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) P262H (PMID: 23680147). 23680147
ERBB3 P262H Advanced Solid Tumor sensitive Pictilisib Preclinical Actionable In a preclinical study, the PI3K inhibitor GDC-0941 inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) P262H (PMID: 23680147). 23680147
ERBB3 act mut Advanced Solid Tumor sensitive Lapatinib Preclinical - Cell culture Actionable In a preclinical study, Tykerb (lapatinib) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) activating mutations (PMID: 23680147). 23680147
ERBB3 V714M Advanced Solid Tumor sensitive Lapatinib Preclinical - Cell culture Actionable In a preclinical study, Tykerb (lapatinib) inhibited cell proliferation in transformed cell lines expressing ERBB3 (HER3) V714M in culture (PMID: 23680147). 23680147
ERBB3 V714M Advanced Solid Tumor sensitive Pertuzumab Preclinical - Cell culture Actionable In a preclinical study, Perjeta (pertuzumab) inhibited cell proliferation in transformed cell lines expressing ERBB3 (HER3) V714M in culture (PMID: 23680147). 23680147
ERBB3 V714M Advanced Solid Tumor sensitive Trastuzumab Preclinical - Cell culture Actionable In a preclinical study, Herceptin (trastuzumab) inhibited cell proliferation in transformed cell lines expressing ERBB3 (HER3) V714M in culture (PMID: 23680147). 23680147
ERBB3 Q809R Advanced Solid Tumor sensitive Trastuzumab Preclinical Actionable In a preclinical study, Herceptin (trastuzumab) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) Q809R (PMID: 23680147). 23680147
ERBB3 A232V Advanced Solid Tumor sensitive Pertuzumab Preclinical - Cell culture Actionable In a preclinical study, Perjeta (pertuzumab) inhibited cell proliferation in transformed cell lines expressing ERBB3 (HER3) A232V in culture (PMID: 23680147). 23680147
ERBB3 P262H Advanced Solid Tumor resistant Cetuximab Preclinical Actionable In a preclinical study, transformed cell lines expressing ERBB3 (HER3) P262H demonstrated resistance to treatment with Erbitux (cetuximab) (PMID: 23680147). 23680147
ERBB3 T389K Advanced Solid Tumor sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) T389K (PMID: 23680147). 23680147
ERBB3 P262H Advanced Solid Tumor sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) P262H (PMID: 23680147). 23680147
ERBB3 Q809R Advanced Solid Tumor sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) Q809R (PMID: 23680147). 23680147
ERBB3 Q809R Advanced Solid Tumor decreased response Pertuzumab Preclinical Actionable In a preclinical study, transformed cell lines expressing ERBB3 (HER3) Q809R in culture demonstrated a decreased response to Perjeta (pertuzumab), showing inhibition of proliferation and colony formation, but to a lesser degree than other therapies (PMID: 23680147). 23680147
ERBB3 P262H Advanced Solid Tumor sensitive Pertuzumab Preclinical Actionable In a preclinical study, Perjeta (pertuzumab) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) P262H (PMID: 23680147). 23680147
ERBB3 P262H Advanced Solid Tumor sensitive Trastuzumab Preclinical Actionable In a preclinical study, Herceptin (trastuzumab) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) P262H (PMID: 23680147). 23680147
ERBB3 G284R Advanced Solid Tumor sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) G284R (PMID: 23680147). 23680147
ERBB3 G284R Advanced Solid Tumor sensitive Pertuzumab Preclinical Actionable In a preclinical study, Perjeta (pertuzumab) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) G284R (PMID: 23680147). 23680147
ERBB3 T389K Advanced Solid Tumor sensitive Pertuzumab Preclinical - Cell culture Actionable In a preclinical study, Perjeta (pertuzumab) inhibited cell proliferation in transformed cell lines expressing ERBB3 (HER3) T389K in culture (PMID: 23680147). 23680147
ERBB3 A232V Advanced Solid Tumor sensitive Trastuzumab Preclinical - Cell culture Actionable In a preclinical study, Herceptin (trastuzumab) inhibited cell proliferation in transformed cell lines expressing ERBB3 (HER3) A232V in culture (PMID: 23680147). 23680147
ERBB3 Q809R Advanced Solid Tumor sensitive PD-0325901 + Pictilisib Preclinical Actionable In a preclinical study, the combination of GDC-0941 and PD-0325901 (PI3K and MEK inhibitors, respectively) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) Q809R (PMID: 23680147). 23680147
ERBB3 V104M Advanced Solid Tumor sensitive Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) inhibited cell proliferation in transformed cell lines expressing ERBB3 (HER3) V104M in culture (PMID: 23680147). 23680147
ERBB3 Q809R Advanced Solid Tumor decreased response Pictilisib Preclinical Actionable In a preclinical study, transformed cell lines expressing ERBB3 (HER3) Q809R in culture demonstrated a decreased response to Pictlisib (GDC-0941), showing inhibition of proliferation and colony formation, but to a lesser degree than other therapies (PMID: 23680147). 23680147
ERBB3 P262H Advanced Solid Tumor sensitive Duligotuzumab Preclinical Actionable In a preclinical study, MEHD7945A inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) P262H (PMID: 23680147). 23680147
ERBB3 V104M Advanced Solid Tumor sensitive Pertuzumab Preclinical - Cell culture Actionable In a preclinical study, Perjeta (pertuzumab) inhibited cell proliferation in transformed cell lines expressing ERBB3 (HER3) V104M in culture (PMID: 23680147). 23680147
ERBB3 G284R Advanced Solid Tumor sensitive PD-0325901 + Pictilisib Preclinical Actionable In a preclinical study, the combination of GDC-0941 and PD-0325901 (PI3K and MEK inhibitors, respectively) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) G284R (PMID: 23680147). 23680147
ERBB3 Q809R Advanced Solid Tumor sensitive Duligotuzumab Preclinical Actionable In a preclinical study, MEHD7945A inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) Q809R (PMID: 23680147). 23680147
ERBB3 T389K Advanced Solid Tumor sensitive Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) inhibited cell proliferation in transformed cell lines expressing ERBB3 (HER3) T389K in culture (PMID: 23680147). 23680147
ERBB3 A232V Advanced Solid Tumor sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) A232V (PMID: 23680147). 23680147
ERBB3 A232V Advanced Solid Tumor sensitive Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) inhibited cell proliferation in transformed cell lines expressing ERBB3 (HER3) A232V in culture (PMID: 23680147). 23680147
ERBB3 G284R Advanced Solid Tumor sensitive Pictilisib Preclinical Actionable In a preclinical study, the PI3K inhibitor GDC-0941 inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) G284R (PMID: 23680147). 23680147
ERBB3 V104M Advanced Solid Tumor sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) V104M (PMID: 23680147). 23680147
ERBB3 T389K Advanced Solid Tumor sensitive Trastuzumab Preclinical - Cell culture Actionable In a preclinical study, Herceptin (trastuzumab) inhibited cell proliferation in transformed cell lines expressing ERBB3 (HER3) T389K in culture (PMID: 23680147). 23680147
ERBB3 V104M Advanced Solid Tumor sensitive Trastuzumab Preclinical - Cell culture Actionable In a preclinical study, Herceptin (trastuzumab) inhibited cell proliferation in transformed cell lines expressing ERBB3 (HER3) V104M in culture (PMID: 23680147). 23680147
ERBB3 G284R Advanced Solid Tumor sensitive Trastuzumab Preclinical Actionable In a preclinical study, Herceptin (trastuzumab) inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) G284R (PMID: 23680147). 23680147
ERBB3 G284R Advanced Solid Tumor resistant Cetuximab Preclinical Actionable In a preclinical study, transformed cell lines expressing ERBB3 (HER3) G284R demonstrated resistance to treatment with Erbitux (cetuximab) (PMID: 23680147). 23680147
ERBB3 G284R Advanced Solid Tumor sensitive Duligotuzumab Preclinical Actionable In a preclinical study, MEHD7945A inhibited proliferation and colony formation in transformed cell lines expressing ERBB3 (HER3) G284R (PMID: 23680147). 23680147