Non-Small Cell Lung Cancer Targeted Therapy: Drugs and Mechanisms of Drug Resistance

Abstract

The advent of precision medicine has brought light to the treatment of non-small cell lung cancer (NSCLC), expanding the options for patients with advanced NSCLC by targeting therapy through genetic and epigenetic cues. Tumor driver genes in NSCLC patients have been uncovered one by one, including epidermal growth factor receptor (EGFR), mesenchymal lymphoma kinase (ALK), and receptor tyrosine kinase ROS proto-oncogene 1 (ROS1) mutants. Antibodies and inhibitors that target the critical gene-mediated signaling pathways that regulate tumor growth and development are anticipated to increase patient survival and quality of life. Targeted drugs continue to emerge, with as many as two dozen approved by the FDA, and chemotherapy and targeted therapy have significantly improved patient prognosis. However, resistance due to cancer drivers' genetic alterations has given rise to significant challenges in treating patients with metastatic NSCLC. Here, we summarized the main targeted therapeutic sites of NSCLC drugs and discussed their resistance mechanisms, aiming to provide new ideas for follow-up research and clues for the improvement of targeted drugs.

Keywords: EGFR; NSCLC; drug resistance; molecular mechanisms; targeted therapy.

Figure 1

Genes and pathways associated with targeted drugs for NSCLC. Four critical signaling pathways include JAK-STAT, MAPK, PLC-gamma (phospho-lipase C gamma), and PI3K-AKT. These pathways are well-known controllers of cell cycle progression, proliferation, and apoptosis/cell survival; deregulation is a frequent characteristic of human malignancies. Alterations in key pathways will affect DNA methylation modifications, such as increased DNA methyltransferases (DNMTs) and decreased the ten-eleven translocation methylcytosine dioxygenases (TETs), further allowing overexpression of mesenchymal homology box 2 (MEOX2), whose expression is negatively correlated with patient survival. Additionally, post-translational histone modifications were affected. As shown in the figure, histone acetyltransferases (HATs), histone deacetylases (HDACs, also known as lysine deacetylases or KDACs), the lysine methyltransferases (KMTs) and lysine demethylases (KDMs) undergo corresponding up- or downregulation, affecting the expression of P21, P53, nuclear factor κB (NFκB), and other related proteins that are closely related to the cell cycle. Non-coding RNAs, such as long non-coding RNAs (LncRNAs) and miRNAs, are produced as a result of abnormal transcription. The lncRNA is a brand-new class of regulatory RNA. The LncRNA HOX antisense intergenic RNA (HOTAIR), an oncogene in NSCLC, is one of the significant factors controlling the growth of malignancies. Unknown are the immunomodulatory pathway and probable molecular mechanism involved in NSCLC. Notably, the graphic labels current FDA-approved medications that target EGFR, ALK, MET, RET, VEGF, NTRK, ROS1, KRAS, and BRAF.

Figure 2

Mechanisms and frequency of resistance to EGFR-TKIs. MET gene amplification, PIK3CA gene mutations, bypass pathway activation, downstream pathway activation, EGFR modification mutations or amplification, and development of small cell lung cancer are examples of resistance mechanisms to EGFR-TKIs (SCLC). Third-generation EGFR-TKIs used as first-line therapy result in C797S mutations.

Figure 3

BRAF medication resistance mechanisms and mutation probability. BRAF mutations resulted in altered mitogen-activated protein kinase (MAPK) molecules. The approximate frequencies of frequent driver mutations discovered in the MAPK pathway in lung cancer are shown on the left side of the figure. BRAF valence at codon 600 (V600E) mutations, which cause native activation of BRAF, is only found in 1–2% of lung cancers. In patients with activating BRAF mutations, clinical study of BRAF alone or in combination with downstream MEK inhibition is continuing. On the right, prominent BRAF inhibitors are described. BRAF inhibitor resistance is conferred through cRAF, ARAF, the MAP kinase family member COT, and the pro-survival members of the BCL-2 family MCL-1. Despite BRAF inhibition, increased production of the alternative RAF isoforms (ARAP and CRAF) and MAP3K8/COT can still activate the MAPK pathway. The PI3K and MAPK pathways, which may offer paths around BRAF inhibition and apoptosis, also activate MCL-1.