Novel oncogenic RET mutation found in small cell lung cancer

For the first time an oncogenic somatic mutation at amino acid 918 in the RET (rearranged during transfection) protein has been identified in small cell lung cancer (SCLC) tumors and enforced expression of this mutation within SCLC cell lines produced increased intracellular signaling and cell growth.

SCLC is a highly malignant form of lung cancer representing 15% of all lung cancers and is strongly associated with tobacco smoking. NSCLC, representing 85% of lung cancer, 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 there are no approved targeted therapies for SCLC.

Investigators at Case 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.

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), 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.

The authors say that their work “suggests that RET mutations play a potential role in some cases of SCLC as no other activating mutations were identified among the 19 oncogenes assayed in the tumor harboring the RET M918T mutation, potentially making 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”.

Co-author Dr. Shahab Babakoohi is a member of IASLC..

Cancer that started in the lung

If your cancer started in the lung, it is a primary lung cancer. There are several different types and these are divided into two main groups

  Small cell lung cancer
  Non small cell lung cancer

Small cell lung cancer

About 12 out of every 100 lung cancers diagnosed are this type (12%). Small cell lung cancer is called this because under the microscope the cancer cells look small and are mostly filled with the nucleus (the control centre of cells). It is also called oat cell cancer. This type of cancer is usually caused by smoking. It is very rare for someone who has never smoked to develop it. Small cell lung cancer often spreads quite early on and so your doctors may recommend chemotherapy treatment rather than surgery.

Non small cell lung cancer

There are three common types of non small cell lung cancer. These are grouped together because they behave in a similar way and respond to treatment in a different way to small cell lung cancer. They make up about 87 out of 100 lung cancers in the UK (87%). The three types are

  Squamous cell carcinoma
  Large cell carcinoma

Novel oncogenic RET mutation found in small cell lung cancer Occasionally it is not possible to work out which type of non small cell lung cancer you have. It may not be possible to tell if only a few cells are taken during a biopsy. It can also be difficult if the cells are very undeveloped. Undeveloped cancer cells are known as undifferentiated cells. So your doctor will say that you have undifferentiated non small cell lung cancer. This will not usually make any difference to your treatment, because most non small cell lung cancers are treated in the same way.


About the IASLC:

The International Association for the Study of Lung Cancer (IASLC) is the only global organization dedicated to the study of lung cancer. Founded in 1974, the association’s membership includes more than 4,000 lung cancer specialists in 80 countries.


Murry W. Wynes, PhD
IASLC Special Projects Manager
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(720) 325-2945

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