For the first time an oncogenic somatic mutation at amino acid 918 in the Rearranged During Transfection or RET protein has been identified in Small Cell Lung Cancer or SCLC tumors and enforced expression of this mutation within SCLC cell lines produced increased intracellular signaling and cell growth.
Small Cell Lung Cancer or SCLC is a highly malignant form of lung cancer. The disease represents approximately 15% of all lung cancers and is strongly associated with tobacco smoking. Based on information in the Surveillance, Epidemiologic, and End Results or SEER database, the overall incidence and mortality rates of SCLC in the United States has decreased over the last 30 years.[1] This year, the estimated number of new cases from lung cancer, combining the both SCLC and Non-small Cell Lung Cancer or NSCLC is 2014 are 224,210 with a total of estimated deaths of 159,260.[1][2]
…RET mutations may play a potential role in some cases of SCLC since no other activating mutations were identified among the 19 oncogenes assayed in the tumor harboring the RET M918T mutation…
SCLC Diagnosis
At the time of diagnosis, approximately 30% of patients with SCLC will have tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited-stage disease or LD.[3] Patients with tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease or ED.
Non-Small Cell Lung Cancer
Non-Small Cell Lung Cancer or NSCLC, on the other hand, a disease representing 85% of all lung cancers, has been extensively examined for genomic alterations and targeted therapies are approved for patients with certain mutations, however SCLC has not been examined with the same rigor and – to date – there are no approved targeted therapies for SCLC.
RET wild type and mutant protein
Investigators atCase Western University examined 6 SCLC tumors, 3 each from primary and metastatic tumors, for 238 somatic mutations across 19 oncogenes. RET wild type and mutant protein was then overexpressed in SCLC cell lines and these cell lines were examined for cell signaling, cell growth and responsiveness to two tyrosine kinase inhibitors of RET.
Tyrosine Kinase Inhibitors
Results reported in the September issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer (IASLC), the only global organization dedicated to the study of lung cancer founded in 1974, revealed the RET M918T mutation in a metastatic SCLC tumor and that overexpression of this mutant protein in SCLC cell lines resulted in increased ERK signaling, MYC expression and increased cell proliferation. Likewise, these cell lines overexpressing the RET protein became sensitive to ponatinib and vandetanib, tyrosine kinase inhibitors of RET. Decreased cell growth was the result of this inhibition of RET. [4]
Commenting on their work, the authors say that RET mutations may play a potential role in some cases of SCLC since no other activating mutations were identified among the 19 oncogenes assayed in the tumor harboring the RET M918T mutation. This could potentially make M918T the driver mutation in this tumor. However, the authors caution that the role of oncogenic RET mutations cannot be judged fairly until a larger number of tumors are genomically analyzed, including metastatic tumors.[4]
Clinical trials
Patients diagnosed with SCLC should consider taking part in one of the many clinical trials being conducted to improve treatment. Clinical trials are taking place in most parts of the country and around the world for patients with all stages of small cell lung cancer.
For more information:
[1] Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, Spitznagel EL, Piccirillo J. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006 Oct 1;24(28):4539-44.[Article][PubMed]
[2] Murray N, Coy P, Pater JL, Hodson I, Arnold A, Zee BC, Payne D, Kostashuk EC, Evans WK, Dixon P, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1993 Feb;11(2):336-44.[Article][PubMed]
[3] American Cancer Society (ACS). Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Last accessed on August 22, 2014 [Download PDF]
[4] Dabir S, Babakoohi S, Kluge A, Morrow JJ, Kresak A, Yang M, MacPherson D, Wildey G, Dowlati A. RET Mutation and Expression in Small-Cell Lung Cancer. J Thorac Oncol. 2014 Sep;9(9):1316-23. doi: 10.1097/JTO.0000000000000234.[Article][PubMed]
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