Reference Detail

Ref Type Journal Article
PMID (22046346)
Authors Kancha RK, von Bubnoff N, Bartosch N, Peschel C, Engh RA, Duyster J
Title Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib.
Journal PloS one
Vol 6
Issue 10
Date 2011
URL
Abstract Text Overexpression of the ERBB2 kinase is observed in about one-third of breast cancer patients and the dual ERBB1/ERBB2 kinase inhibitor lapatinib was recently approved for the treatment of advanced ERBB2-positive breast cancer. Mutations in the ERBB2 receptor have recently been reported in breast cancer at diagnosis and also in gastric, colorectal and lung cancer. These mutations may have an impact on the clinical responses achieved with lapatinib in breast cancer and may also have a potential impact on the use of lapatinib in other solid cancers. However, the sensitivity of lapatinib towards clinically observed ERBB2 mutations is not known.We cloned a panel of 8 clinically observed ERBB2 mutations, established stable cell lines and characterized their sensitivity towards lapatinib and alternative ERBB2 inhibitors. Both lapatinib-sensitive and lapatinib-resistant ERBB2 mutations were observed. Interestingly, we were able to generate lapatinib resistance mutations in wt-ERBB2 cells incubated with lapatinib for prolonged periods of time. This indicates that these resistance mutations may also cause secondary resistance in lapatinib-treated patients. Lapatinib-resistant ERBB2 mutations were found to be highly resistant towards AEE788 treatment but remained sensitive towards the dual irreversible inhibitors CL-387785 and WZ-4002.Patients harbouring certain ERBB2 kinase domain mutations at diagnosis may not benefit from lapatinib treatment. Moreover, secondary lapatinib resistance may develop due to kinase domain mutations. Irreversible ERBB2 inhibitors may offer alternative treatment options for breast cancer and other solid tumor patients harbouring lapatinib resistance mutations. In addition, these inhibitors may be of interest in the scenario of secondary lapatinib resistance.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
H878Y missense gain of function ERBB2 (HER2) H878Y lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). H878Y confers a gain of function to the Erbb2 (Her2) protein as demonstrated by increased Erbb2 (Her2) phosphorylation and transformation of cells in cell culture (PMID: 22046346).
L755P missense gain of function ERBB2 (HER2) L755P lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). L755P results in increased phosphorylation of Erbb2 (Her2), activation of downstream signaling, and is transforming in cell culture (PMID: 22046346, PMID: 29967253).
L755S missense gain of function ERBB2 (HER2) L755S lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). L755S results in increased phosphorylation of Erbb2 (Her2), activation of downstream signaling, is transforming in cell culture (PMID: 29967253), and is associated with resistance to Erbb2 (Her2)-targeted therapies (PMID: 22046346, PMID: 28487443). Y
N857S missense gain of function ERBB2 (HER2) N857S lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). N857S results in constitutive phosphorylation of Erbb2 (Her2) and is transforming in cell culture (PMID: 22046346).
T798M missense gain of function ERBB2 (HER2) T798M lies within the gatekeeper position in the ATP binding site of the Erbb2 (HER2) protein. T798M results in activation of the Erbb2 (Her2) protein in cell culture experiments (PMID: 22046346, PMID: 23948973) and demonstrates the ability to increase cell proliferation and cell viability in culture (PMID: 29533785).
T862A missense gain of function ERBB2 (HER2) T862A lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). T862A results in constitutive phosphorylation of Erbb2 (Her2) and is transforming in cell culture (PMID: 22046346, PMID: 29533785, PMID: 29967253).
V773A missense gain of function ERBB2 (HER2) V773A lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). V773A results in constitutive phosphorylation of Erbb2 (Her2) and is transforming in cell culture (PMID: 22046346).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 T862A Advanced Solid Tumor sensitive AEE788 Preclinical Actionable In a preclinical study, AEE788 inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) T862A in culture (PMID: 22046346). 22046346
ERBB2 L755S Advanced Solid Tumor resistant Lapatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ERBB2 L755S demonstrated resistance when treated with Tykerb (lapatinib) in culture (PMID: 22046346). 23220880 22046346
ERBB2 L755S Advanced Solid Tumor sensitive WZ4002 Preclinical Actionable In a preclinical study, WZ4002 inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) L755S in culture (PMID: 22046346). 22046346
ERBB2 H878Y Advanced Solid Tumor sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) H878Y in culture (PMID: 22046346). 22046346
ERBB2 L755P Advanced Solid Tumor sensitive EKI-285 Preclinical Actionable In a preclinical study, EKI-285 (CL-387785) inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) L755P in culture (PMID: 22046346). 22046346
ERBB2 V777L Advanced Solid Tumor sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) V777L in culture (PMID: 22046346). 22046346
ERBB2 L755S Advanced Solid Tumor sensitive EKI-285 Preclinical Actionable In a preclinical study, EKI-285 (CL-387785) inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) L755S in culture (PMID: 22046346). 22046346
ERBB2 V773A Advanced Solid Tumor sensitive AEE788 Preclinical Actionable In a preclinical study, AEE788 inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) V773A in culture (PMID: 22046346). 22046346
ERBB2 wild-type Advanced Solid Tumor sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) inhibited proliferation of transformed cell lines expressing wild-type ERBB2 (HER2) in culture (PMID: 22046346). 22046346
ERBB2 V777L Advanced Solid Tumor sensitive AEE788 Preclinical Actionable In a preclinical study, transformed cell lines expressing ERBB2 (HER2) V777L demonstrated growth inhibition when treated with AEE788 in culture (PMID: 22046346). 22046346
ERBB2 T798M Advanced Solid Tumor sensitive EKI-285 Preclinical Actionable In a preclinical study, EKI-285 (CL-387785) inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) T798M in culture (PMID: 22046346). 22046346
ERBB2 L755P Advanced Solid Tumor sensitive WZ4002 Preclinical Actionable In a preclinical study, WZ4002 inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) L755P in culture (PMID: 22046346). 22046346
ERBB2 H878Y Advanced Solid Tumor sensitive AEE788 Preclinical Actionable In a preclinical study, transformed cell lines expressing ERBB2 (HER2) H878Y demonstrated growth inhibition when treated with AEE788 in culture (PMID: 22046346). 22046346
ERBB2 T798M Advanced Solid Tumor resistant AEE788 Preclinical Actionable In a preclinical study, transformed cell lines expressing ERBB2 (HER2) T798M demonstrated resistance when treated with AEE788 in culture (PMID: 22046346). 22046346
ERBB2 L755P Advanced Solid Tumor resistant AEE788 Preclinical Actionable In a preclinical study, transformed cell lines expressing ERBB2 (HER2) L755P demonstrated resistance when treated with AEE788 in culture (PMID: 22046346). 22046346
ERBB2 L755P Advanced Solid Tumor resistant Lapatinib Preclinical Actionable In a preclinical study, transformed cell lines expressing ERBB2 (HER2) L755P demonstrated resistance when treated with Tykerb (lapatinib) in culture (PMID: 22046346). 22046346
ERBB2 T862A Advanced Solid Tumor decreased response Lapatinib Preclinical Actionable In a preclinical study, higher dose of Tykerb (lapatinib) inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) N862A in culture (PMID: 22046346). 22046346
ERBB2 N857S Advanced Solid Tumor decreased response Lapatinib Preclinical Actionable In a preclinical study, higher dose of Tykerb (lapatinib) inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) N857S in culture (PMID: 22046346). 22046346
ERBB2 V773A Advanced Solid Tumor decreased response Lapatinib Preclinical Actionable In a preclinical study, higher dose of Tykerb (lapatinib) inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) V773A in culture (PMID: 22046346). 22046346
ERBB2 T798M Advanced Solid Tumor sensitive WZ4002 Preclinical Actionable In a preclinical study, WZ4002 inhibited proliferation of transformed cell lines expressing ERBB2 (HER2) T798M in culture (PMID: 22046346). 22046346
ERBB2 act mut Advanced Solid Tumor sensitive AEE788 Preclinical Actionable In a preclinical study, transformed cells expressing ERBB2 (HER2) activation loop mutations demonstrated sensitivity to AEE788 in culture (PMID: 22046346). 22046346
ERBB2 T798M Advanced Solid Tumor resistant Lapatinib Preclinical Actionable In a preclinical study, transformed cell lines expressing ERBB2 (HER2) T798M demonstrated resistance when treated with Tykerb (lapatinib) in culture (PMID: 22046346). 22046346
ERBB2 N857S Advanced Solid Tumor sensitive AEE788 Preclinical Actionable In a preclinical study, AEE788 inhibited proliferation of transformed cell lines expressing ERBB2(HER2) N857S in culture (PMID: 22046346). 22046346
ERBB2 wild-type Advanced Solid Tumor sensitive AEE788 Preclinical Actionable In a preclinical study, AEE788 inhibited proliferation of transformed cell lines expressing wild-type ERBB2 (HER2) in culture (PMID: 22046346). 22046346
ERBB2 L755S Advanced Solid Tumor resistant AEE788 Preclinical Actionable In a preclinical study, transformed cell lines expressing ERBB2 (HER2) L755S demonstrated resistance to AEE788 in culture, except at very high doses (PMID: 22046346). 22046346