Researchers have identified additional driver mutations in non–small cell lung cancer that may guide the development of new targeted drugs and immunotherapy. The findings also highlight key differences between two major NSCLC subtypes that could inform future therapeutic strategies.

A comprehensive genomic analysis of non–small cell lung cancer (NSCLC) has identified additional driver mutations that may guide the development of new targeted drugs and immunotherapy. The findings also highlight key differences between subtypes of NSCLC that could inform future therapeutic management strategies (Nat Genet 2016;48:607–16).

The study researchers profiled two major subtypes of NSCLC via whole-exome sequencing: 660 lung adenocarcinoma (ADC) and 484 lung squamous cell carcinoma (SCC) samples. They found multiple mutated genes along the RAS–RAF signaling pathway that had not been associated with lung ADC, including SOS1, RASA1, and VAV1.

Current targeted therapy research in lung ADC is largely focused on inhibiting receptor tyrosine kinases, including EGFR, that activate RAS–RAF signaling and are often mutated in this disease. The discovery of previously unknown players along a main driver pathway in lung ADC extends the realm of possible therapeutic targets, says senior author Matthew Meyerson, MD, PhD, professor of pathology at Dana-Farber Cancer Institute in Boston, MA. It also underscores the importance of using large sample sizes in genomic studies, he adds. For example, SOS1 was already known to be mutated in patients with Noonan syndrome, a genetic disorder, but previous smaller studies failed to identify it in lung ADCs.

The team also found that 47% of lung ADC and 53% of lung SCC samples had at least five neoepitopes—peptides arising from somatic tumor mutations—that could potentially be targeted by cancer vaccines. The identification of these neoepitopes suggests that in NSCLC, a significant fraction of tumors may respond to immune checkpoint inhibitors, Meyerson observes.

Additionally, he says, this study shows that the two main NSCLC subtypes are more distinct than previously thought. Of 38 mutated genes detected in the lung ADC samples, and 20 detected in lung SCCs, only six were shared by both subtypes. In fact, the mutations and amplifications noted in lung SCC were found to be more similar to other cancers associated with smoking—including head and neck SCC and bladder cancer—than to lung ADC.

“It indicates that there are some very similar pathway abnormalities and mutations that accompany squamous cell tumors, regardless of where they originate,” says Stephen Baylin, MD, co-director of the cancer biology research program at the Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD. “As such, there may be common management strategies that could be used to treat these types of cancer.”

Further research is needed into the role of neoepitopes in immunotherapy, Meyerson notes. “We need to understand the relationship between neoepitopes, especially recurrent ones, and patient responses to immune checkpoint inhibitors,” he says. “Future studies should seek to determine whether predicted cancer neoepitopes are in fact leading to immune responses in lung cancer.” –Janet Colwell

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©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.