title: RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.
abstract: Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Niederst
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Poirier
authors.affiliation: 1] Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group, 415 Main Street, Cambridge, Massachusetts 02142, USA [2] Department of Pathology, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Craig H
authors.initials: CH
authors.lastname: Mermel
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Lockerman
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Angel R
authors.initials: AR
authors.lastname: Garcia
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katayama
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Costa
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Ross
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Moran
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Howe
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Linnea E
authors.initials: LE
authors.lastname: Fulton
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Hillary E
authors.initials: HE
authors.lastname: Mulvey
authors.affiliation: 1] Department of Pathology, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Pathology, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Bernardo
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Farhiya
authors.initials: F
authors.lastname: Mohamoud
authors.affiliation: 1] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA [2] Molecular Profiling Laboratory, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Norikatsu
authors.initials: N
authors.lastname: Miyoshi
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: VanderLaan
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.affiliation: 1] Department of Medical Oncology, Belfer Institute of Applied Science, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Borger
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA [3] Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: 1] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA [2] Molecular Profiling Laboratory, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Toshi
authors.initials: T
authors.lastname: Shioda
authors.affiliation: 1] Department of Pathology, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Pathology, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: 1] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA [2] Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group, 415 Main Street, Cambridge, Massachusetts 02142, USA [3] Department of Pathology, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: 1] Department of Pathology, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Pathology, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D012008:Recurrence; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; C494811:BCL2L1 protein, human; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D016160:Retinoblastoma Protein; D013449:Sulfonamides; D051020:bcl-X Protein; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib; C528561:navitoclax