Current Molecular-Targeted Therapies in NSCLC and Their Mechanism of Resistance

Abstract

Lung cancer is treated with many conventional therapies, such as surgery, radiation, and chemotherapy. However, these therapies have multiple undesirable side effects. To bypass the side effects elicited by these conventional treatments, molecularly-targeted therapies are currently in use or under development. Current molecularly-targeted therapies effectively target specific biomarkers, which are commonly overexpressed in lung cancers and can cause increased tumorigenicity. Unfortunately, several molecularly-targeted therapies are associated with initial dramatic responses followed by acquired resistance due to spontaneous mutations or activation of signaling pathways. Acquired resistance to molecularly targeted therapies presents a major clinical challenge in the treatment of lung cancer. Therefore, to address this clinical challenge and to improve lung cancer patient prognosis, we need to understand the mechanism of acquired resistance to current therapies and develop additional novel therapies. This review concentrates on various lung cancer biomarkers, including EGFR, ALK, and BRAF, as well as their potential mechanisms of drug resistance.

Keywords: TKI; inhibitor; lung cancer; molecularly-targeted therapies; resistance.

Figure 1

Mechanisms of resistance to molecularly targeted therapies in non-small cell lung cancer (NSCLC). Phosphorylation of receptor tyrosine kinases such as ALK, c-MET, and EGFR lead to activation of downstream signaling pathways that are responsible for cell proliferation, survival, and angiogenesis. Receptor tyrosine kinase inhibitors (TKIs) inhibit receptor activation. However, due to mutations listed in the figure and activation of alternative signaling pathways, tumor cells acquire resistance against these TKIs. Activation of PI3K/mTOR, Wnt, and RAS-MAPK pathways may cause resistance to TKIs. Dimerization of IGF-1R with EGFR may activate the Akt and MAPK pathways despite inhibition.

Figure 2

EMT, MET amplification, and IGF-1R confer resistance to EGFR TKIs. Dimerization with IGF-1R allows activation of the MAPK and PI3K pathways despite EGFR inhibition. MET amplification allows phosphorylation of EGFR and activation of downstream signaling. Activation of the Hedgehog signaling pathway and Wnt signaling pathways promote EMT, which may confer resistance to EGFR TKIs.

Figure 3

CRAF, ARAF, COT, and MCL-1 confer resistance to BRAF inhibitors. Elevated expression of alternative RAF isoforms (ARAF and CRAF), as well as MAP3K8/COT, can stimulate the MAPK pathway despite BRAF inhibition. The PI3K and MAPK pathways also activate MCL-1 and may provide a route to escape apoptosis and bypass BRAF inhibition.