Reference Detail

Ref Type Journal Article
PMID (23948973)
Authors Rexer BN, Ghosh R, Narasanna A, Estrada MV, Chakrabarty A, Song Y, Engelman JA, Arteaga CL
Title Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 19
Issue 19
Date 2013 Oct 01
URL
Abstract Text Mutations in receptor tyrosine kinase (RTK) genes can confer resistance to receptor-targeted therapies. A T798M mutation in the HER2 oncogene has been shown to confer resistance to the tyrosine kinase inhibitor (TKI) lapatinib. We studied the mechanisms of HER2-T798M-induced resistance to identify potential strategies to overcome that resistance.HER2-T798M was stably expressed in BT474 and MCF10A cells. Mutant cells and xenografts were evaluated for effects of the mutation on proliferation, signaling, and tumor growth after treatment with combinations of inhibitors targeting the EGFR/HER2/HER3/PI3K axis.A low 3% allelic frequency of the T798M mutant shifted 10-fold the IC50 of lapatinib. In mutant-expressing cells, lapatinib did not block basal phosphorylation of HER2, HER3, AKT, and ERK1/2. In vitro kinase assays showed increased autocatalytic activity of HER2-T798M. HER3 association with PI3K p85 was increased in mutant-expressing cells. BT474-T798M cells were also resistant to the HER2 antibody trastuzumab. These cells were sensitive to the pan-PI3K inhibitors BKM120 and XL147 and the irreversible HER2/EGFR TKI afatinib but not the MEK1/2 inhibitor CI-1040, suggesting continued dependence of the mutant cells on ErbB receptors and downstream PI3K signaling. BT474-T798M cells showed increased expression of the EGFR ligands EGF, TGFα, amphiregulin, and HB-EGF. Addition of the EGFR neutralizing antibody cetuximab or lapatinib restored trastuzumab sensitivity of BT474-T798M cells and xenografts, suggesting that increased EGFR ligand production was causally associated with drug resistance.Simultaneous blockade of HER2 and EGFR should be an effective treatment strategy against HER2 gene-amplified breast cancer cells harboring T798M mutant alleles.

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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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
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).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 T798M Her2-receptor positive breast cancer resistant Lapatinib Preclinical Actionable In a preclinical study, ERBB2 (HER2)-receptor positive breast cancer cells expressing ERBB2 (HER2) T798M were resistant to Tykerb (lapatinib) in both culture and xenograft models (PMID: 23948973). 23948973
ERBB2 T798M breast cancer sensitive Lapatinib + Trastuzumab Preclinical - Cell line xenograft Actionable In a preclinical study, human breast cancer cell lines and cell line xenografts expressing ERBB2 T798M demonstrated sensitivity to the combination of Herceptin (trastuzumab) and Tykerb (lapatinib) (PMID: 23948973). 23948973
ERBB2 amp ERBB2 T798M breast cancer resistant Trastuzumab Preclinical - Cell line xenograft Actionable In a preclinical study, a human ERBB2-amplified breast cancer cell line expressing ERBB2 (HER2) T798M was resistant to Herceptin (trastuzumab) in culture and in xenograft models (PMID: 23948973). 23948973
ERBB2 T798M breast cancer sensitive Cetuximab + Lapatinib Preclinical - Cell line xenograft Actionable In preclinical studies, the combination of Erbitux (cetuximab) and Tykerb (lapatinib) inhibited cell growth of a human breast cancer cell line harboring ERBB2 T798M and synergized to inhibit tumor growth in xenograft models (PMID: 23948973). 23948973
ERBB2 T798M breast cancer sensitive Afatinib Preclinical Actionable In a preclinical study, breast cancer cells expressing ERBB2(HER2) T798M were sensitive to Gilotrif (afatinib) (PMID: 23948973). 23948973
ERBB2 T798M breast cancer sensitive Buparlisib Preclinical Actionable In a preclinical study, human breast cancer cells expressing the ERBB2 (HER2) T798M mutation demonstrated sensitivity to BKM120 (PMID: 23948973). 23948973
ERBB2 T798M breast cancer sensitive XL147 Preclinical Actionable In a preclinical study, breast cancer cell lines expressing ERBB2 (HER2) T798M demonstrated sensitivity to XL147 (SAR245408) in cell culture (PMID: 23948973). 23948973
ERBB2 T798M breast cancer resistant CI-1040 Preclinical Actionable In a preclinical study, breast cancer cells expressing ERBB2 T798M demonstrated resistance to CI-1040 (PMID: 23948973). 23948973
ERBB2 T798M breast cancer sensitive Trastuzumab + XL147 Preclinical Actionable In a preclinical study, breast cancer cells expressing ERBB2 (HER2) T798M were sensitive to the combination of Herceptin (trastuzumab) and XL147 (PMID: 23948973). 23948973
ERBB2 T798M breast cancer resistant Cetuximab Preclinical Actionable In a preclinical study, breast cancer cells expressing the ERBB2 (HER2) T798M mutant were resistant to Erbitux (cetuximab)(PMID: 23948973). 23948973