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An Acquired Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer.
Hanker AB, Brewer MR, Sheehan JH, Koch JP, Sliwoski GR, Nagy R, Lanman R, Berger MF, Hyman DM, Solit DB, He J, Miller V, Cutler RE, Lalani AS, Cross D, Lovly CM, Meiler J, Arteaga CL
(2017) Cancer Discov 7: 575-585
MeSH Terms: Afatinib, Antineoplastic Agents, Breast Neoplasms, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Humans, Middle Aged, Mutation, Phenotype, Protein Kinase Inhibitors, Quinazolines, Quinolines, Receptor, ErbB-2
Show Abstract · Added April 8, 2017
We report a gatekeeper mutation in a patient with -mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2 reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2 but not HER2 In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2-induced signaling and cell growth. Acquisition of HER2 upon development of resistance to neratinib in a breast cancer with an initial activating mutation suggests is a driver mutation. HER2-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. We found an acquired gatekeeper mutation in a patient with -mutant breast cancer upon clinical progression on neratinib. We speculate that may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with -activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. .
©2017 American Association for Cancer Research.
1 Communities
3 Members
0 Resources
14 MeSH Terms
EGFR Kinase Domain Duplication (EGFR-KDD) Is a Novel Oncogenic Driver in Lung Cancer That Is Clinically Responsive to Afatinib.
Gallant JN, Sheehan JH, Shaver TM, Bailey M, Lipson D, Chandramohan R, Red Brewer M, York SJ, Kris MG, Pietenpol JA, Ladanyi M, Miller VA, Ali SM, Meiler J, Lovly CM
(2015) Cancer Discov 5: 1155-63
MeSH Terms: Adult, Afatinib, Antineoplastic Agents, Drug Resistance, Neoplasm, ErbB Receptors, Gene Duplication, Gene Frequency, Humans, Lung Neoplasms, Male, Models, Molecular, Molecular Targeted Therapy, Mutation, Neoplasm Staging, Protein Conformation, Protein Interaction Domains and Motifs, Protein Kinase Inhibitors, Protein Multimerization, Quinazolines, Tomography, X-Ray Computed, Treatment Outcome
Show Abstract · Added January 26, 2016
UNLABELLED - Oncogenic EGFR mutations are found in 10% to 35% of lung adenocarcinomas. Such mutations, which present most commonly as small in-frame deletions in exon 19 or point mutations in exon 21 (L858R), confer sensitivity to EGFR tyrosine kinase inhibitors (TKI). In analyzing the tumor from a 33-year-old male never-smoker, we identified a novel EGFR alteration in lung cancer: EGFR exon 18-25 kinase domain duplication (EGFR-KDD). Through analysis of a larger cohort of tumor samples, we detected additional cases of EGFR-KDD in lung, brain, and other cancers. In vitro, EGFR-KDD is constitutively active, and computational modeling provides potential mechanistic support for its auto-activation. EGFR-KDD-transformed cells are sensitive to EGFR TKIs and, consistent with these in vitro findings, the index patient had a partial response to the EGFR TKI afatinib. The patient eventually progressed, at which time resequencing revealed an EGFR-dependent mechanism of acquired resistance to afatinib, thereby validating EGFR-KDD as a driver alteration and therapeutic target.
SIGNIFICANCE - We identified oncogenic and drug-sensitive EGFR-KDD that is recurrent in lung, brain, and soft-tissue cancers and documented that a patient with metastatic lung adenocarcinoma harboring the EGFR-KDD derived significant antitumor response from treatment with the EGFR inhibitor afatinib. Findings from these studies will be immediately translatable, as there are already several approved EGFR inhibitors in clinical use.
©2015 American Association for Cancer Research.
1 Communities
5 Members
0 Resources
21 MeSH Terms
Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer.
Meador CB, Jin H, de Stanchina E, Nebhan CA, Pirazzoli V, Wang L, Lu P, Vuong H, Hutchinson KE, Jia P, Chen X, Eisenberg R, Ladanyi M, Politi K, Zhao Z, Lovly CM, Cross DA, Pao W
(2015) Mol Cancer Ther 14: 542-52
MeSH Terms: Acrylamides, Afatinib, Aged, Aniline Compounds, Animals, Antibodies, Monoclonal, Humanized, Cell Line, Tumor, Cell Proliferation, Cetuximab, Drug Resistance, Neoplasm, ErbB Receptors, Humans, Lung Neoplasms, Male, Mice, Nude, Molecular Targeted Therapy, Mutation, Quinazolines
Show Abstract · Added February 13, 2015
Metastatic EGFR-mutant lung cancers are sensitive to the first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, and afatinib, but resistance develops. Acquired resistance to gefitinib or erlotinib occurs most commonly (>50%) via the emergence of a second-site EGFR mutation, T790M. Two strategies to overcome T790M-mediated resistance are dual inhibition of EGFR with afatinib plus the anti-EGFR antibody cetuximab (A+C), or mutant-specific EGFR inhibition with AZD9291. A+C and AZD9291 are now also being tested as first-line therapies, but whether these therapies will extend progression-free survival or induce more aggressive forms of resistance in this setting remains unknown. We modeled resistance to multiple generations of anti-EGFR therapies preclinically to understand the effects of sequential treatment with anti-EGFR agents on drug resistance and determine the optimal order of treatment. Using a panel of erlotinib/afatinib-resistant cells, including a novel patient-derived cell line (VP-2), we found that AZD9291 was more potent than A+C at inhibiting cell growth and EGFR signaling in this setting. Four of four xenograft-derived A+C-resistant cell lines displayed in vitro and in vivo sensitivity to AZD9291, but four of four AZD9291-resistant cell lines demonstrated cross-resistance to A+C. Addition of cetuximab to AZD9291 did not confer additive benefit in any preclinical disease setting. This work, emphasizing a mechanistic understanding of the effects of therapies on tumor evolution, provides a framework for future clinical trials testing different treatment sequences. This paradigm is applicable to other tumor types in which multiple generations of inhibitors are now available.
©2014 American Association for Cancer Research.
0 Communities
2 Members
0 Resources
18 MeSH Terms
Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1.
Pirazzoli V, Nebhan C, Song X, Wurtz A, Walther Z, Cai G, Zhao Z, Jia P, de Stanchina E, Shapiro EM, Gale M, Yin R, Horn L, Carbone DP, Stephens PJ, Miller V, Gettinger S, Pao W, Politi K
(2014) Cell Rep 7: 999-1008
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Afatinib, Animals, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Tumor, Cetuximab, Drug Resistance, Neoplasm, ErbB Receptors, Humans, Lung Neoplasms, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Nude, Mice, Transgenic, Multiprotein Complexes, Mutation, Quinazolines, Random Allocation, TOR Serine-Threonine Kinases, Xenograft Model Antitumor Assays
Show Abstract · Added May 27, 2014
Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation tyrosine kinase inhibitors (TKIs) develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
0 Communities
2 Members
0 Resources
22 MeSH Terms
Targeted therapies: Afatinib--new therapy option for EGFR-mutant lung cancer.
Yu HA, Pao W
(2013) Nat Rev Clin Oncol 10: 551-2
MeSH Terms: Afatinib, Carcinoma, Non-Small-Cell Lung, ErbB Receptors, Humans, Lung Neoplasms, Molecular Targeted Therapy, Mutation, Quinazolines
Added September 3, 2013
0 Communities
2 Members
0 Resources
8 MeSH Terms
HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation.
Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, Ohashi K, Janjigian YY, Spitzler PJ, Melnick MA, Riely GJ, Kris MG, Miller VA, Ladanyi M, Politi K, Pao W
(2012) Cancer Discov 2: 922-33
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Afatinib, Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Cell Line, Tumor, Cetuximab, Class I Phosphatidylinositol 3-Kinases, Drug Resistance, Neoplasm, ErbB Receptors, Erlotinib Hydrochloride, Humans, Lung Neoplasms, Mice, Mice, Nude, Molecular Targeted Therapy, Mutation, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Kinase Inhibitors, Quinazolines, RNA Interference, RNA, Small Interfering, Receptor, ErbB-2
Show Abstract · Added September 3, 2013
EGF receptor (EGFR)-mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKI). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models and human patients. Because afatinib is also a potent HER2 inhibitor, we investigated the role of HER2 in EGFR-mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. FISH analysis revealed that HER2 was amplified in 12% of tumors with acquired resistance versus only 1% of untreated lung adenocarcinomas. Notably, HER2 amplification and EGFR(T790M) were mutually exclusive. Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR-TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR-mutant tumors with acquired resistance to EGFR-TKIs.
0 Communities
2 Members
0 Resources
26 MeSH Terms
Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.
Regales L, Gong Y, Shen R, de Stanchina E, Vivanco I, Goel A, Koutcher JA, Spassova M, Ouerfelli O, Mellinghoff IK, Zakowski MF, Politi KA, Pao W
(2009) J Clin Invest 119: 3000-10
MeSH Terms: Afatinib, Amphiregulin, Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Cetuximab, Disease Models, Animal, Drug Resistance, Neoplasm, EGF Family of Proteins, Epidermal Growth Factor, Epiregulin, ErbB Receptors, Erlotinib Hydrochloride, Gene Expression Profiling, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Lung Neoplasms, Male, Mice, Mice, Nude, Mice, Transgenic, Mutation, Neoplasm Transplantation, Paclitaxel, Protein Kinase Inhibitors, Quinazolines, Transplantation, Heterologous, Tumor Cells, Cultured
Show Abstract · Added March 24, 2014
EGFR is a major anticancer drug target in human epithelial tumors. One effective class of agents is the tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. These drugs induce dramatic responses in individuals with lung adenocarcinomas characterized by mutations in exons encoding the EGFR tyrosine kinase domain, but disease progression invariably occurs. A major reason for such acquired resistance is the outgrowth of tumor cells with additional TKI-resistant EGFR mutations. Here we used relevant transgenic mouse lung tumor models to evaluate strategies to overcome the most common EGFR TKI resistance mutation, T790M. We treated mice bearing tumors harboring EGFR mutations with a variety of anticancer agents, including a new irreversible EGFR TKI that is under development (BIBW-2992) and the EGFR-specific antibody cetuximab. Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance. Moreover, this approach could serve as an important model for targeting other receptor tyrosine kinases activated in human cancers.
0 Communities
1 Members
0 Resources
30 MeSH Terms
Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma.
Bean J, Riely GJ, Balak M, Marks JL, Ladanyi M, Miller VA, Pao W
(2008) Clin Cancer Res 14: 7519-25
MeSH Terms: Adenocarcinoma, Afatinib, Aged, Amino Acid Sequence, Antineoplastic Agents, Base Sequence, Cell Line, Tumor, Drug Resistance, Neoplasm, ErbB Receptors, Erlotinib Hydrochloride, Female, Gefitinib, Humans, Immunoblotting, Lung Neoplasms, Molecular Sequence Data, Mutation, Polymerase Chain Reaction, Polymorphism, Restriction Fragment Length, Protein Kinase Inhibitors, Protein Structure, Quaternary, Quinazolines, Sequence Alignment
Show Abstract · Added March 24, 2014
PURPOSE - Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are associated with sensitivity of lung adenocarcinomas to the EGFR tyrosine kinase inhibitors, gefitinib and erlotinib. Acquired drug resistance is frequently associated with a secondary somatic mutation that leads to the substitution of methionine for threonine at position 790 (T790M). We aimed to identify additional second-site alterations associated with acquired resistance.
EXPERIMENTAL DESIGN - Tumor samples were obtained from 48 patients with acquired resistance. Tumor cell DNA was analyzed for EGFR kinase domain mutations. Molecular analyses were then done to characterize the biological properties of a novel mutant EGFR allele.
RESULTS - A previously unreported mutation in exon 21 of EGFR, which leads to substitution of alanine for threonine at position 854 (T854A), was identified in one patient with a drug-sensitive EGFR L858R-mutant lung adenocarcinoma after long-term treatment with tyrosine kinase inhibitors. The T854A mutation was not detected in a pretreatment tumor sample. The crystal structure analyses of EGFR suggest that the T854 side chain is within contact distance of gefitinib and erlotinib. Surrogate kinase assays show that the EGFR T854A mutation abrogates the inhibition of tyrosine phosphorylation by erlotinib. Such resistance seems to be overcome by a new irreversible dual EGFR/HER2 inhibitor, BIBW 2992.
CONCLUSIONS - The T854A mutation is the second reported second-site acquired resistance mutation that is within contact distance of gefitinib and erlotinib. These data suggest that acquired resistance to ATP-mimetic EGFR kinase inhibitors may often be associated with amino acid substitutions that alter drug contact residues in the EGFR ATP-binding pocket.
0 Communities
1 Members
0 Resources
23 MeSH Terms