Oncogenic alterations in advanced NSCLC: a molecular super-highway

Abstract

Lung cancer ranks among the most common cancers world-wide and is the first cancer-related cause of death. The classification of lung cancer has evolved tremendously over the past two decades. Today, non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma, comprises a multitude of molecular oncogenic subsets that change both the prognosis and management of disease.Since the first targeted oncogenic alteration identified in 2004, with the epidermal growth factor receptor (EGFR), there has been unprecedented progress in identifying and targeting new molecular alterations. Almost two decades of experience have allowed scientists to elucidate the biological function of oncogenic drivers and understand and often overcome the molecular basis of acquired resistance mechanisms. Today, targetable molecular alterations are identified in approximately 60% of lung adenocarcinoma patients in Western populations and 80% among Asian populations. Oncogenic drivers are largely enriched among non-smokers, east Asians, and younger patients, though each alteration has its own patient phenotype.The current landscape of druggable molecular targets includes EGFR, anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog B (BRAF), ROS proto-oncogene 1 (ROS1), Kirstin rat sarcoma virus (KRAS), human epidermal receptor 2 (HER2), c-MET proto-oncogene (MET), neurotrophic receptor tyrosine kinase (NTRK), rearranged during transfection (RET), neuregulin 1 (NRG1). In addition to these known targets, others including Phosphoinositide 3-kinases (PI3K) and fibroblast growth factor receptor (FGFR) have garnered significant attention and are the subject of numerous ongoing trials.In this era of personalized, precision medicine, it is of paramount importance to identify known or potential oncogenic drivers in each patient. The development of targeted therapy is mirrored by diagnostic progress. Next generation sequencing offers high-throughput, speed and breadth to identify molecular alterations in entire genomes or targeted regions of DNA or RNA. It is the basis for the identification of the majority of current druggable alterations and offers a unique window into novel alterations, and de novo and acquired resistance mechanisms.In this review, we discuss the diagnostic approach in advanced NSCLC, focusing on current oncogenic driver alterations, through their pathophysiology, management, and future perspectives. We also explore the shortcomings and hurdles encountered in this rapidly evolving field.

Fig. 1

Incidence of oncogenic driver alterations in advanced non-small-cell lung adenocarcinoma. RET: rearranged during transfection, ERBB2: human epidermal growth factor receptor 2, BRAF: B-raf murine sarcoma viral homolog B, ROS1: ROS proto-oncogene 1, MET: c-Met, amp: amplification, ALK: anaplastic lymphoma kinase, EGFR: epidermal growth factor receptor, KRAS: Kirsten rat sarcoma

Fig. 2

FDA timeline of drug approvals. Since 2003, there has been a rapid acceleration of drug development and approvals for molecular targeted therapies in NSCLC. Today, both kinase inhibitors and antibody–drug conjugates are approved

Fig. 3

EMA timeline of drug approvals. Since 2003, there has been a rapid acceleration of drug development and approvals for molecular targeted therapies in NSCLC. Today, both kinase inhibitors and antibody–drug conjugates are approved