Novel Oncogenic RET Mutation Found in Small Cell Lung Cancer

Editor’s note: An oncologist will sometimes test a patient’s tumor for specific mutations in order to decide what the best treatment options are. Tumors that have certain mutations can sometimes be treated with certain so-called targeted therapy drugs. This approach has worked well for many people with non-small cell lung cancer (NSCLC). However, there are no FDA-approved targeted therapies for small cell lung cancer (SCLC). A new discovery might change that. Researchers found a mutation called RET M918T in a metastatic SCLC tumor. Two targeted drugs were found to fight against tumor cells with the mutation in the lab. The drugs—ponatinib and vandetanib—are already FDA-approved to treat other types of cancer.

“For the first time, an oncogenic somatic mutation at amino acid 918 in the rearranged during transfection protein has been identified in small cell lung cancer tumors and enforced expression of this mutation within small cell lung cancer tumor 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.”


Online Screening for Rare Lung Cancer Subtypes Opens Door to New Kind of Clinical Trial

Editor’s note: This article discusses a new clinical trial—a research study that is enrolling volunteer patients. The goal of the trial is to enroll lung cancer patients whose tumors have mutations in the FGFR1 gene, and to see how well the FGFR1-targeted drug ponatinib works for them. The FGFR1 mutation is rare, so the researchers behind the trial are spreading the word to patients through the internet, with the help of participating organizations.

“In the previous few years, several breakthrough treatments have become available for key subtypes of lung cancer. Patients who may benefit from these treatments can be pre-identified by looking for defined genetic abnormalities in their cancer. For example, patients whose lung cancer is driven by rearrangement of the gene ALK derive significant benefit from the drug crizotinib, which targets this abnormality. Many ongoing clinical trials are now attempting to replicate this success by matching different drugs with specific subtypes of the disease based on the presence of such “predictive biomarkers.” However, testing these new drugs in clinical trials requires finding and enrolling patients with what may be very rare molecular subtypes of a disease – one of the challenges is discovering enough needles in enough haystacks to prove the effectiveness of each biomarker-drug pairing.

“The University of Colorado Cancer Center is now taking a novel approach to this problem, reaching out via the internet to expand the pool of patients potentially eligible for just such a biomarker-preselected clinical trial. After completing the interactive online screening questions, eligible patients with advanced lung cancer will be consented via the phone to permit a pre-existing biopsy sample of their lung cancer tissue to be shipped to the CU Cancer Center for trial-specific molecular testing. The testing is designed to identify patients who may have lung cancers driven by alterations in the gene FGFR1. Patients whose tumors turn out to be FGFR1-positive and meet the other trial screening criteria will then be offered treatment for their cancer within a clinical trial at CU Cancer Center using the experimental FGFR1 inhibitor drug ponatinib. Ponatinib is already licensed for treating certain blood cancers, but work by CU scientists in laboratory models suggest it may also be a potent agent in some specific molecular subtypes of lung cancer driven by, among other things, changes in the FGFR1 gene.”


RET Mutations May Emerge as New Target for Lung Cancer Treatments

A certain type of mutation in a protein, called RET, occurs in a significant subset of lung cancer patients, a recent study shows. Known as ‘rearrangements,’ these mutations fuse the RET gene with other nearby genes, resulting in a RET protein that contains parts of other proteins and is hyperactive. Patients with similar rearrangement mutations in another gene, ALK, can experience drastic improvements from treatment with ALK inhibitors such as crizotinib (Xalkori). This raises the hope that patients with RET rearrangement mutations may be similarly helped by drugs that block RET–either novel RET inhibitors or existing tyrosine kinase inhibitors (TKIs), such as vandetanib (Caprelsa), sunitinib (Sutent), sorafenib (Nexavar), or ponatinib (Iclusig). Identifying patients who may benefit from such treatments would be made easier by the new test for RET mutations developed by the study’s authors. When examining a group of patients with lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC), who did not have mutations in other cancer-relevant genes, the researchers found that 15% had RET rearrangement mutations.


Iclusig Inhibits Mutant Proteins Found in Lung Cancer

The leukemia drug ponatinib (Iclusig) also appears to target mutant versions of two proteins involved in non-small cell lung cancer (NSCLC). This is supported by two recent studies in which Iclusig slowed the growth of cells with mutant RET and FGFR proteins. The drug also shrank tumors with RET mutations that had been grown in mice. Based on these findings, Iclusig manufacturer ARIAD Pharmaceuticals is planning a phase II clinical trial to investigate the drug’s effectiveness against NSCLC with RET mutations. A phase II trial assessing Iclusig’s effects in squamous cell carcinoma (SCC) of the lung with FGFR mutations is already underway at the Dana-Farber Cancer Institute, Boston, Massachusetts, and is currently enrolling participants.


ARIAD Presents New Preclinical Data Showing Ponatinib is a Potent Inhibitor of RET and FGFR, Two Oncogenic Drivers of Non-Small Cell Lung Cancer

ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced the presentation of preclinical data on ponatinib (Iclusig™) , at the American Association for Cancer Research (AACR) Annual Meeting 2013, in Washington. In separate studies, ponatinib is shown to potently inhibit RET, a clinically proven oncogenic driver of medullary thyroid cancer (MTC) and non-small cell lung cancer (NSCLC), and FGFR, which is commonly mutated in endometrial, lung and other cancers…”