title: Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.
abstract: Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Hata
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Niederst
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Archibald
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Gomez-Caraballo
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Faria M
authors.initials: FM
authors.lastname: Siddiqui
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Hillary E
authors.initials: HE
authors.lastname: Mulvey
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.|Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Yosef E
authors.initials: YE
authors.lastname: Maruvka
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Ji
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Hyo-eun C
authors.identifier: http://orcid.org/0000-0003-1892-7093
authors.initials: HE
authors.lastname: Bhang
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Viveksagar
authors.initials: V
authors.lastname: Krishnamurthy Radhakrishna
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.|Candiolo Cancer Institute-Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Siravegna
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Haichuan
authors.initials: H
authors.lastname: Hu
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sana
authors.initials: S
authors.lastname: Raoof
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lockerman
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Anuj
authors.initials: A
authors.lastname: Kalsy
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Lee
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Celina L
authors.initials: CL
authors.lastname: Keating
authors.affiliation: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Ruddy
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Damon
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Crystal
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Costa
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Piotrowska
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.|Candiolo Cancer Institute-Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Ruslan I
authors.initials: RI
authors.lastname: Sadreyev
authors.affiliation: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Stegmeier
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.|Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.|Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Virginia Commonwealth University Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry, Richmond, Virginia, USA.|Virginia Commonwealth University Massey Cancer Center, Richmond, Virginia, USA.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Faber
authors.affiliation: Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
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