RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer

Matthew J Niederst; Lecia V Sequist; John T Poirier; Craig H Mermel; Elizabeth L Lockerman; Angel R Garcia; Ryohei Katayama; Carlotta Costa; Kenneth N Ross; Teresa Moran; Emily Howe; Linnea E Fulton; Hillary E Mulvey; Lindsay A Bernardo; Farhiya Mohamoud; Norikatsu Miyoshi; Paul A VanderLaan; Daniel B Costa; Pasi A Jänne; Darrell R Borger; Sridhar Ramaswamy; Toshi Shioda; Anthony J Iafrate; Gad Getz; Charles M Rudin; Mari Mino-Kenudson; Jeffrey A Engelman

doi:10.1038/ncomms7377

RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer

Nat Commun. 2015 Mar 11:6:6377. doi: 10.1038/ncomms7377.

Authors

Matthew J Niederst¹, Lecia V Sequist¹, John T Poirier², Craig H Mermel³, Elizabeth L Lockerman¹, Angel R Garcia¹, Ryohei Katayama¹, Carlotta Costa¹, Kenneth N Ross¹, Teresa Moran¹, Emily Howe¹, Linnea E Fulton¹, Hillary E Mulvey¹, Lindsay A Bernardo⁴, Farhiya Mohamoud¹, Norikatsu Miyoshi⁵, Paul A VanderLaan⁶, Daniel B Costa⁷, Pasi A Jänne⁸, Darrell R Borger¹, Sridhar Ramaswamy⁹, Toshi Shioda⁵, Anthony J Iafrate⁴, Gad Getz¹⁰, Charles M Rudin², Mari Mino-Kenudson⁴, Jeffrey A Engelman¹

Affiliations

¹ 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.
² Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service, 1275 York Avenue, New York, New York 10065, USA.
³ 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.
⁴ 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.
⁵ 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.
⁶ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
⁷ Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
⁸ 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.
⁹ 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.
¹⁰ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenocarcinoma / drug therapy
Adenocarcinoma / genetics*
Adenocarcinoma / metabolism
Adenocarcinoma / pathology
Adenocarcinoma of Lung
Afatinib
Aniline Compounds / pharmacology
Antineoplastic Agents / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Disease Progression
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / deficiency
ErbB Receptors / genetics*
Erlotinib Hydrochloride / pharmacology
Gefitinib
Gene Expression Regulation, Neoplastic
Humans
Lung / drug effects
Lung / metabolism
Lung / pathology
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Mutation
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
Quinazolines / pharmacology
Recurrence
Retinoblastoma Protein / deficiency
Retinoblastoma Protein / genetics*
Signal Transduction
Small Cell Lung Carcinoma / drug therapy
Small Cell Lung Carcinoma / genetics*
Small Cell Lung Carcinoma / metabolism
Small Cell Lung Carcinoma / pathology
Sulfonamides / pharmacology
bcl-X Protein / genetics
bcl-X Protein / metabolism

Substances

Aniline Compounds
Antineoplastic Agents
BCL2 protein, human
BCL2L1 protein, human
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-bcl-2
Quinazolines
Retinoblastoma Protein
Sulfonamides
bcl-X Protein
Afatinib
Erlotinib Hydrochloride
EGFR protein, human
ErbB Receptors
Gefitinib
navitoclax

Associated data

GEO/GSE64322
GEO/GSE64765
GEO/GSE64766

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding