Reference Detail

Ref Type

Journal Article

PMID

(25122427)

Authors

Dabir S, Babakoohi S, Kluge A, Morrow JJ, Kresak A, Yang M, MacPherson D, Wildey G, Dowlati A

Title

RET mutation and expression in small-cell lung cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer	9	9	2014 Sep	1316-23	J Thorac Oncol

URL

Abstract Text

There is growing interest in defining the somatic mutations associated with small-cell lung cancer (SCLC). Unfortunately, a serious blockade to genomic analyses of this disease is a limited access to tumors because surgery is rarely performed. We used our clinical/pathologic database of SCLC patients to determine the availability of biopsy specimens that could be used for genomic studies and to identify tumors for initial oncogene analysis.DNA was extracted from six tumors, three primary and three metastatic, and analyzed by SEQUENOM platform technology.Primary-resected tumor tissue represents less than 3% of all diagnostic specimens in this disease, highlighting the limited access to tissue sufficient for comprehensive genomic analyses. We identified an activating M918T RET somatic mutation in a metastatic SCLC tumor specimen. Bioinformatic search identified RET mutations in other SCLC studies. Stable overexpression of both mutant M918T and wild-type RET in two SCLC cell lines, H1048 and SW1271, activated ERK signaling, MYC expression, and increased cell proliferation, particularly by mutant RET. Stable cells became sensitized to the RET tyrosine kinase inhibitors, vandetanib and ponatinib. Further analysis of RET mRNA expression in SCLC revealed wide variability in both cells and tumors, and SCLC cells demonstrated significantly higher RET expression compared with adenocarcinoma lung cells.Our data suggest that a subpopulation of SCLC patients may derive benefit from tyrosine kinase inhibitors targeting RET. Coupled with the presence of RET fusion proteins in non-small-cell lung cancer, our data indicate an emerging role for RET in SCLC.

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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

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRIP1	A745P	missense	unknown	BRIP1 A745P does not lie within any known functional domains of the Brip1 protein (UniProt.org). A745P has been identified in sequencing studies (PMID: 25122427), but has not been characterized and therefore, its effect on Brip1 protein function is unknown (PubMed, Feb 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET wild-type	lung small cell carcinoma	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited growth of small cell lung carcinoma lines expressing wild-type RET (PMID: 25122427).	25122427
RET M918T	lung small cell carcinoma	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited growth of small cell lung carcinoma lines expressing RET M918T (PMID: 25122427).	25122427
RET wild-type	lung small cell carcinoma	sensitive	Vandetanib	Preclinical	Actionable	In a preclinical study, Caprelsa (vandetanib) inhibited growth of small cell lung carcinoma lines expressing wild-type RET (PMID: 25122427).	25122427
RET M918T	lung small cell carcinoma	sensitive	Vandetanib	Preclinical	Actionable	In a preclinical study, Caprelsa (vandetanib) inhibited growth of small cell lung carcinoma lines expressing RET M918T (PMID: 25122427).	25122427