Recent progress in targeted therapy for non-small cell lung cancer

Abstract

The high morbidity and mortality of non-small cell lung cancer (NSCLC) have always been major threats to people's health. With the identification of carcinogenic drivers in non-small cell lung cancer and the clinical application of targeted drugs, the prognosis of non-small cell lung cancer patients has greatly improved. However, in a large number of non-small cell lung cancer cases, the carcinogenic driver is unknown. Identifying genetic alterations is critical for effective individualized therapy in NSCLC. Moreover, targeted drugs are difficult to apply in the clinic. Cancer drug resistance is an unavoidable obstacle limiting the efficacy and application of targeted drugs. This review describes the mechanisms of targeted-drug resistance and newly identified non-small cell lung cancer targets (e.g., KRAS G12C, NGRs, DDRs, CLIP1-LTK, PELP1, STK11/LKB1, NFE2L2/KEAP1, RICTOR, PTEN, RASGRF1, LINE-1, and SphK1). Research into these mechanisms and targets will drive individualized treatment of non-small cell lung cancer to generate better outcomes.

Keywords: CLIP1-LTK; NSCLC; drug resistance; non-small cell lung cancer; targeted therapy.

FIGURE 1

The resistance mechanisms of existing targeted therapies, and the examples of corresponding mechanisms.

FIGURE 2

The carcinogenic pathways were affected by these emerging targets. NGRs, CLIP1-LTK fusion, DDR mutation and YES1 activate the MAPK pathway and the PI3K pathway, which can affect cell proliferation and differentiation, etc. KRAS G12C mutation and RASGRF1 fusion affect the dissociation of RAS protein from GTP, which in turn activates the MAPK pathway and exerts carcinogenic effects. When PTEN was mutated, the PI3K pathway was continuously activated and exerts carcinogenic effects. PINK1 exerts a carcinogenic effect by activating AKT, thereby activating the downstream signaling pathway. LKB1 cannot activate AMPK when it is mutated, and cannot negatively regulate the mTOR pathway, which, like RICTOR amplification, causes excessive activation of the mTOR pathway and plays a carcinogenic role.

FIGURE 3

The carcinogenic effect of NFE2L2/KEAP1 mutation, PELP1, LINE-1-FGGY, SphK1 and BMI1. When NFE2L2/KEAP1 was mutated, NRF2 cannot be degraded, and NRF2 binds to antioxidative response element (ARE) to produce antioxidant factors that resist the therapeutic effects of radiotherapy. LINE-1-FGGY promotes cell proliferation and invasion by influencing the AA metabolic pathway as well as the Wnt pathway. BMI1 promotes cell transfer and invasion by influencing EMT. The binding of PELP1 to STAT3 promotes the expression of c-myc, cyclin D1, c-fos, and thus promotes cell proliferation. Elevated SphK1 activity promotes S1P production, which binds to corresponding receptors and promotes the production of Bcl-2, MMP2 and cyclin D, thereby promoting cell proliferation and metastasis.