RET mutation identified as potential novel target in SCLC

Issue: December 10, 2014

The newly identified RET M918T somatic mutation in small cell lung cancer exhibited widely variable expression and was associated with increased cell proliferation, according to study results.

Ponatinib (Iclusig, Ariad) and vandetanib (Caprelsa, AstraZeneca) — tyrosine kinase inhibitors that target RET — may therefore provide a new therapeutic option in this setting, researchers wrote.

Snehal Dabir, PhD, of the division of hematology and oncology of Case Western Reserve University and University Hospitals Case Medical Center, and colleagues sought to define somatic mutations associated with small cell lung cancer (SCLC). There has been a lack of genomic data from SCLC tumors since few of these patients undergo surgery, according to background information provided by the researchers.

Dabir and colleagues sequenced genomic data from three metastatic and three primary tumors from their clinical/pathological database of SCLC patients. Researchers noted that only 2.7% of all specimens were surgical samples from the first diagnostic specimen, and all of these samples were from patients with limited disease.

Researchers detected an activating RET M918T mutation in one metastatic tumor specimen. They then scanned other SCLC studies and identified additional RET mutations in four tumors and two cell lines.

Further analyses indicated overexpression of RET M918T was associated with increased ERK signaling, MYC expression and increased cell proliferation. Cell lines with overexpressed RET M918T were sensitive to ponatinib and vandetanib.

When researchers compared these data with a gene array analysis of 15 SCLC tumors, they found RET expression varied 272-fold among the tumors.

Furthermore, compared with non–small cell lung cancer (NSCLC) cells, SCLC cells demonstrated significantly greater RET mRNA expression (P˂.05). However, expression was comparable between SCLC cells and squamous or large-cell carcinoma cells.

These data highlight the need for more genomic analyses in SCLC, as has been accomplished in NSCLC, the researchers wrote.

“Our data support a view that the lack of progress in therapeutic innovation in SCLC can be traced back to a lack of sufficient tumor tissue required for throughout genomic and proteomic studies,” Dabir and colleagues wrote. “Furthermore, the genomic data of surgically resected SCLC primary tumors may not be representative of the disease, particularly when considering recent evidence that tumors evolve during metastasis. Thus, it is essential to capture more genomic data on metastatic SCLC tumors to obtain a full view of this disease.”

Disclosure: The researchers report no relevant financial disclosures.

Published by:

Sources/Disclosures

Collapse

Source: Dabir S. J Thorac Oncol. 2014;9:1316-1323.