New targetable oncogenes in non-small-cell lung cancer

Abstract

The identification of oncogenic driver mutations underlying sensitivity to epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors has led to a surge of interest in identifying additional targetable oncogenes in non-small-cell lung cancer. A number of new potentially oncogenic gene alterations have been characterized in recent years, including BRAF mutations, HER2 insertions, PIK3CA mutations, FGFR1 amplifications, DDR2 mutations, ROS1 rearrangements, and RET rearrangements. In this review, we will discuss the techniques used to discover each of these candidate oncogenes, the prevalence of each in non-small-cell lung cancer, the preclinical data supporting their role in lung cancer, and data on small molecular inhibitors in development.

Fig 1.

Prevalence of new targetable oncogenes in non–small-cell lung cancer. Although several of the individual oncogenic alterations are relatively rare, in total they constitute (A) 9% to 14% of lung adenocarcinomas and (B) 16% to 30% of squamous cell lung carcinomas.

Fig 2.

Strategies used to identify targetable oncogenes in non–small-cell lung cancer (NSCLC). (A) Alterations in recognized proto-oncogenes (eg, BRAF mutations) can be identified through focused sequencing efforts. (B) Unexpected oncogenes (eg, FGFR1 or ALK) can be discovered through genome-wide screening strategies, with the requirement that initial positive results are subsequently confirmed in a separate cohort of clinical specimens. (C) Analysis of specimens from a trial of a targeted therapy (eg, epidermal growth factor receptor [EGFR] tyrosine kinase inhibitors [TKIs]) has the advantage of being inherently tied to an available treatment, although there may be limitations to what genomic analyses are feasible on biopsies from patients with advanced NSCLC. All candidate oncogenes should demonstrate oncogenicity in a model system before they can be considered driver mutations.