Molecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer

Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide. The discovery of tyrosine kinase inhibitors effectively targeting EGFR mutations in lung cancer patients in 2004 represented the beginning of the precision medicine era for this refractory disease. This great progress benefits from the identification of driver gene mutations, and after that, conventional and new technologies such as NGS further illustrated part of the complex molecular pathways of NSCLC. More targetable driver gene mutation identification in NSCLC patients greatly promoted the development of targeted therapy and provided great help for patient outcomes including significantly improved survival time and quality of life. Herein, we review the literature and ongoing clinical trials of NSCLC targeted therapy to address the molecular pathways and targeted intervention progress in NSCLC. In addition, the mutations in EGFR gene, ALK rearrangements, and KRAS mutations in the main sections, and the less common molecular alterations in MET, HER2, BRAF, ROS1, RET, and NTRK are discussed. The main resistance mechanisms of each targeted oncogene are highlighted to demonstrate the current dilemma of targeted therapy in NSCLC. Moreover, we discuss potential therapies to overcome the challenges of drug resistance. In this review, we manage to display the current landscape of targetable therapeutic patterns in NSCLC in this era of precision medicine.

Future perspective for the application of predictive biomarker testing in advanced stage non-small cell lung cancer

“…Resistance mechanisms may involve target-specific or other mechanisms, either within the originally affected or an alternative pathway, and even transformations to other histological subtypes are reported. 27 For example, previously described resistance mechanisms to osimertinib treatment in patients with EGFR -mutated NSCLC include EGFR resistance mutations, MET amplification, amplification of cell cycle genes (e.g., CDK4 ), gene fusions (most commonly RET fusions), and DNA amplification of EGFR . 28 Although some aberrations have been described as a resistance mechanism to different targeted therapies or molecular drivers (i.e., overlapping/common resistance mechanisms), distinct resistance mechanisms to specific therapies or drivers are also reported.…”

Cutting-Edge Therapies for Lung Cancer

“…The discovery of tyrosine kinase inhibitors (TKIs) designed to target EGFR mutations in lung cancer patients marked the inception of the precision medicine era in lung cancer. EGFR TKIs have been designed to target these mutations effectively by inhibiting the activation of the tyrosine kinase domain and disrupting various EGFR-dependent/independent downstream signaling pathways in the lungs [ 9 ]. Currently, there are three generations of clinically available EGFR TKIs, namely the first generation of reversible inhibitors (gefitinib, erlotinib, and icotinib), the second generation of irreversible inhibitors (afatinib, dacomitinib), and the third generation of irreversible inhibitors (osimertinib, almonertinib, and lazertinib) [ 9 ]; some of these inhibitors are listed in Table 1 .…”

“…EGFR TKIs have been designed to target these mutations effectively by inhibiting the activation of the tyrosine kinase domain and disrupting various EGFR-dependent/independent downstream signaling pathways in the lungs [ 9 ]. Currently, there are three generations of clinically available EGFR TKIs, namely the first generation of reversible inhibitors (gefitinib, erlotinib, and icotinib), the second generation of irreversible inhibitors (afatinib, dacomitinib), and the third generation of irreversible inhibitors (osimertinib, almonertinib, and lazertinib) [ 9 ]; some of these inhibitors are listed in Table 1 . Although the first- and second-generation TKIs effectively overcome the effects of EGFR mutations, resistance inevitably develops, primarily due to the emergence of the T790M mutation [ 10 , 11 ].…”

Add fuel to the fire: Inflammation and immune response in lung cancer combined with COVID-19

“…The molecular pathways involved in lung cancer remain poorly defined, but in general, smoking, occupational and environmental exposure, air pollution, ionizing radiation are mainly implicated. The above external factors can induce gene alterations and cell malignant transformation, such as activating oncogenes KRAS, EGFR, ALK1 ( 8 , 9 ) and silencing tumor suppressor genes P53, Rb1, UTX ( 10 , 11 ). In addition, The lungs communicate with the external environment.…”