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.”


Drugs to Avoid in Patients on Tyrosine Kinase Inhibitors

Editor’s note: More and more people with cancer are being treated with drugs known as tyrosine kinase inhibitors (TKIs). As with any other drug, oncologists who prescribe TKIs must be aware of other drugs a patient is taking to ensure there will not be a dangerous drug-drug interaction. Researchers recently published a report outlining known and potential drug-drug interactions between TKIs and other drugs. Oncologists and patients may wish to take these into account when considering cancer treatment with TKIs.

“With the rapid and widespread uptake of tyrosine kinase inhibitors (TKIs) in oncology over the past several years, serious drug–drug interactions are an “increasing risk,” according a new report.

“To guarantee the safe use of TKIs, ‘a drugs review for each patient is needed,’ write Frank G.A. Jansman, PharmD, PhD, from Deventer Hospital in the Netherlands, and colleagues in a review published in the July issue of the Lancet Oncology.

“The review provides a comprehensive overview of known and suspected interactions between TKIs and conventional prescribed drugs, over-the-counter drugs, and herbal medicines.

“All 15 TKIs approved to date by the US Food and Drug Administration or the European Medicines Agency are evaluated.

“They are axitinib (Inlyta, Pfizer), crizotinib (Xalkori, Pfizer), dasatinib (Sprycel, Bristol-Myers Squibb and Otsuka America), erlotinib (Tarceva, Osi Pharmaceuticals), gefitinib (Iressa, AstraZeneca), imatinib (Gleevec, Novartis), lapatinib (Tykerb, GlaxoSmithKline), nilotinib (Tasigna, Novartis), pazopanib (Votrient, GlaxoSmithKline), regorafenib (Stivarga, Bayer), ruxolitinib (Jakafi, Incyte), sorafenib (Nexavar, Bayer), sunitinib (Sutent, Pfizer), vandetanib (Caprelsa, AstraZeneca), and vemurafenib (Zelboraf, Roche).”


Erlotinib, Gefitinib and Vandetanib Inhibit Human Nucleoside Transporters and Protect Cancer Cells from Gemcitabine Cytotoxicity

Combinations of tyrosine kinase inhibitors (TKIs) with gemcitabine have been attempted with little added benefit to patients. We hypothesized that TKIs designed to bind to ATP binding pockets of growth factor receptors also bind to transporter proteins that recognize nucleosides.

 

Vandetanib inhibited hENT1, hENT2, hCNT1, hCNT2 and hCNT3 whereas erlotinib inhibited hENT1 and hCNT3 and gefitinib inhibited hENT1 and hCNT1. The potential for reduced accumulation of nucleoside chemotherapy drugs in tumor tissues due to inhibition of hENTs and/or hCNTs by TKIs indicates that pharmacokinetic properties of these agents must be considered when scheduling TKIs and nucleoside chemotherapy in combination.


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.