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Ref Type Journal Article
PMID (18413839)
Authors Trowe T, Boukouvala S, Calkins K, Cutler RE, Fong R, Funke R, Gendreau SB, Kim YD, Miller N, Woolfrey JR, Vysotskaia V, Yang JP, Gerritsen ME, Matthews DJ, Lamb P, Heuer TS
Title EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 14
Issue 8
Date 2008 Apr 15
URL
Abstract Text Mutations associated with resistance to kinase inhibition are an important mechanism of intrinsic or acquired loss of clinical efficacy for kinase-targeted therapeutics. We report the prospective discovery of ErbB2 mutations that confer resistance to the small-molecule inhibitor lapatinib.We did in vitro screening using a randomly mutagenized ErbB2 expression library in Ba/F3 cells, which were dependent on ErbB2 activity for survival and growth.Lapatinib resistance screens identified mutations at 16 different ErbB2 amino acid residues, with 12 mutated amino acids mapping to the kinase domain. Mutations conferring the greatest lapatinib resistance cluster in the NH2-terminal kinase lobe and hinge region. Structural computer modeling studies suggest that lapatinib resistance is caused by multiple mechanisms; including direct steric interference and restriction of conformational flexibility (the inactive state required for lapatinib binding is energetically unfavorable). ErbB2 T798I imparts the strongest lapatinib resistance effect and is analogous to the epidermal growth factor receptor T790M, ABL T315I, and cKIT T670I gatekeeper mutations that are associated with clinical drug resistance. ErbB2 mutants associated with lapatinib resistance transformed NIH-3T3 cells, including L755S and T733I mutations known to occur in human breast and gastric carcinomas, supporting a direct mechanism for lapatinib resistance in ErbB2-driven human cancers. The epidermal growth factor receptor/ErbB2/vascular endothelial growth factor receptor inhibitor EXEL-7647 was found to inhibit almost all lapatinib resistance-associated mutations. Furthermore, no ErbB2 mutations were found to be associated with EXEL-7647 resistance and lapatinib sensitivity.Taken together, these data suggest potential target-based mechanisms of resistance to lapatinib and suggest that EXEL-7647 may be able to circumvent these effects.

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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
ERBB2 C630Y missense unknown ERBB2 (HER2) C630Y lies within the extracellular domain of the Erbb2 (Her2) protein (UniProt.org). C630Y has been identified in the scientific literature (PMID: 18413839), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020).
ERBB2 D821N missense gain of function - predicted ERBB2 (HER2) D821N lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). D821N is weakly transforming and confers resistance to the Erbb2 (Her2) inhibitor Tykerb (lapatinib) in cell culture (PMID: 18413839) and therefore, is predicted to result in a gain of Erbb2 (Her2) protein function. Y
ERBB2 E717K missense unknown ERBB2 (HER2) E717K lies within the cytoplasmic domain of the Erbb2 (Her2) protein (UniProt.org). E717K has been demonstrated to confer resistance to Tykerb (lapatinib) in cell culture (PMID: 18413839), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020). Y
ERBB2 E719G missense unknown ERBB2 (HER2) E719G lies within the cytoplasmic domain of the Erbb2 (Her2) protein (UniProt.org). E719G is associated with drug resistance in cell culture (PMID: 18413839), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020). Y
ERBB2 E719K missense unknown ERBB2 (HER2) E719K lies within the cytoplasmic domain of the Erbb2 (Her2) protein (UniProt.org). E719K has identified in the scientific literature (PMID: 18413839), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020).
ERBB2 E812K missense unknown ERBB2 (HER2) E812K lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). E812K confers Tykerb (lapatinib) resistance in cell culture (PMID: 18413839), but has not been biochemically characterized, and therefore its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020). Y
ERBB2 L726I missense unknown ERBB2 (HER2) L726I lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). L726I is associated with resistance to Iressa (gefitinib) and Tykerb (lapatinib) in cell culture (PMID: 17638894, PMID: 18413839), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020). Y
ERBB2 L785F missense unknown ERBB2 (HER2) L785F lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). L785F confers Tykerb (lapatinib)-resistance in cell culture (PMID: 18413839), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020). Y
ERBB2 L915M missense unknown ERBB2 (HER2) L915M lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). L915M confers Tykerb (lapatinib)-resistance in cell culture (PMID: 18413839), but has not been biochemically characterized and therefore its effect on Erbb2 (Her2) protein is unknown (PubMed, Apr 2020). Y
ERBB2 P780L missense unknown ERBB2 (HER2) P780L lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). P780L confers resistance to Tykerb (lapatinib) in cell culture (PMID: 18413839), but has not been biochemically characterized and therefore its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020). Y
ERBB2 S1002R missense unknown ERBB2 (HER2) S1002R lies within the cytoplasmic domain of the Erbb2 (Her2) protein (UniProt.org). S1002R confers Tykerb (lapatinib)-resistance in cell culture (PMID: 18413839), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020). Y
ERBB2 S783P missense no effect - predicted ERBB2 (HER2) S783P lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). S783P is predicted to have no effect on Erbb2 (Her2) protein function, as it does not result in increased phosphorylation of Erbb2 (Her2) or downstream targets in cultured cells (PMID: 28164408), however, is associated with Tykerb (lapatinib)-resistance in cell culture (PMID: 18413839). Y
ERBB2 T733I missense no effect - predicted ERBB2 (HER2) T733I lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). T733I has not been biochemically characterized, but has weak transformation activity (PMID: 18413839) and induces similar cell proliferation and cell viability as wild-type Erbb2 (Her2), in two different cell lines (PMID: 29533785) and therefore, it is predicted to have no effect on Erbb2 (Her2) protein function.
ERBB2 T798I missense no effect - predicted ERBB2 (HER2) T798I lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). T798I does not result in activation of Erbb2 (Her2) downstream signaling or transformation of cultured cells, but is associated with resistance to Erbb2 (Her2) inhibitors (PMID: 25238247, PMID: PMID: 28274957, PMID: 18413839) and therefore, it is predicted to have no effect on Erbb2 (Her2) protein function. Y
ERBB2 V839G missense unknown ERBB2 (HER2) V839G lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). V839G confers Tykerb (lapatinib)-resistance in cell culture (PMID: 18413839), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020). Y
ERBB2 Y803N missense unknown ERBB2 (HER2) Y803N lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). Y803N is associated with Tykerb (lapatinib)-resistance in cell culture (PMID: 18413839), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 L785F Advanced Solid Tumor sensitive XL647 Preclinical Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) L785F in culture (PMID: 18413839). 18413839
ERBB2 T798I Advanced Solid Tumor sensitive XL647 Preclinical Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) T798I in culture (PMID: 18413839). 18413839
ERBB2 L915M Advanced Solid Tumor sensitive XL647 Preclinical - Cell culture Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) L915M in culture (PMID: 18413839). 18413839
ERBB2 L726F Advanced Solid Tumor decreased response Lapatinib Preclinical Actionable In a preclinical study, transformed cells over expressing ERBB2 (HER2) L726F demonstrated reduced sensitivity to Tykerb (lapatinib) in culture (PMID: 18413839). 18413839
ERBB2 Y803N Advanced Solid Tumor decreased response Lapatinib Preclinical Actionable In a preclinical study, transformed cells over expressing ERBB2 (HER2) Y803N demonstrated reduced sensitivity to Tykerb (lapatinib) in culture (PMID: 18413839). 18413839
ERBB2 L755S Advanced Solid Tumor sensitive XL647 Preclinical Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) L755S in culture (PMID: 18413839). 18413839
ERBB2 E717K Advanced Solid Tumor decreased response Lapatinib Preclinical Actionable In a preclinical study, transformed cells over expressing ERBB2 (HER2) E717K demonstrated reduced sensitivity to Tykerb (lapatinib) in culture (PMID: 18413839). 18413839
ERBB2 Y803N Advanced Solid Tumor sensitive XL647 Preclinical Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) Y803N in culture (PMID: 18413839). 18413839
ERBB2 V839G Advanced Solid Tumor sensitive XL647 Preclinical Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) V839G in culture (PMID: 18413839). 18413839
ERBB2 P780L Advanced Solid Tumor resistant Lapatinib Preclinical Actionable In a preclinical study, transformed cells expressing ERBB2 (HER2) P780L demonstrated resistance to treatment with Tykerb (lapatinib) (PMID: 18413839). 18413839
ERBB2 E719G Advanced Solid Tumor decreased response Lapatinib Preclinical Actionable In a preclinical study, transformed cells over expressing ERBB2 (HER2) E719G demonstrated reduced sensitivity to Tykerb (lapatinib) in culture (PMID: 18413839). 18413839
ERBB2 L726F Advanced Solid Tumor sensitive XL647 Preclinical - Cell culture Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) L726F in culture (PMID: 18413839). 18413839
ERBB2 E717K Advanced Solid Tumor sensitive XL647 Preclinical Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) E717K in culture (PMID: 18413839). 18413839
ERBB2 T733I Advanced Solid Tumor resistant Lapatinib Preclinical Actionable In a preclinical study, transformed cells expressing ERBB2 (HER2) T733I demonstrated resistance to treatment with Tykerb (lapatinib) (PMID: 18413839). 18413839
ERBB2 L785F Advanced Solid Tumor decreased response Lapatinib Preclinical Actionable In a preclinical study, transformed cells over expressing ERBB2 (HER2) L785F demonstrated reduced sensitivity to Tykerb (lapatinib) in culture (PMID: 18413839). 18413839
ERBB2 S783P Advanced Solid Tumor resistant Lapatinib Preclinical Actionable In a preclinical study, transformed cells over expressing ERBB2 (HER2) S783P were resistant to Tykerb (lapatinib) in culture (PMID: 18413839). 18413839
ERBB2 E812K Advanced Solid Tumor sensitive XL647 Preclinical Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) E812K in culture (PMID: 18413839). 18413839
ERBB2 E812K Advanced Solid Tumor decreased response Lapatinib Preclinical Actionable In a preclinical study, transformed cells over expressing ERBB2 (HER2) E812K demonstrated reduced sensitivity to Tykerb (lapatinib) in culture (PMID: 18413839). 18413839
ERBB2 P780L Advanced Solid Tumor sensitive XL647 Preclinical Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) P780L in culture (PMID: 18413839). 18413839
ERBB2 D821N Advanced Solid Tumor sensitive XL647 Preclinical Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) D821N in culture (PMID: 18413839). 18413839
ERBB2 E719G Advanced Solid Tumor sensitive XL647 Preclinical Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) E719G in culture (PMID: 18413839). 18413839
ERBB2 S783P Advanced Solid Tumor sensitive XL647 Preclinical Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) S783P in culture (PMID: 18413839). 18413839
ERBB2 T733I Advanced Solid Tumor sensitive XL647 Preclinical Actionable In a preclinical study, XL647 inhibited survival of transformed cells over expressing ERBB2 (HER2) T733I in culture (PMID: 18413839). 18413839