New horizons for uncommon mutations in non-small cell lung cancer: BRAF, KRAS, RET, MET, NTRK, HER2

Abstract

The 2004 discovery of EGFR mutations, followed by ALK rearrangements, ushered in a targeted therapy era for advanced non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors targeting gene alterations have substantially improved survival and quality of life for patients with NSCLC. In the last decade, rearrangements of the ROS1 oncogene have been incorporated into healthcare practice that are applicable to another small subgroup of patients who benefit from similar targeted strategies. Recent genome studies of lung adenocarcinoma have identified other possible therapeutic targets, including RET , NTRK fusions, c-MET alterations, and activating mutations in KRAS , BRAF , and HER2, all with frequencies greater than 1%. Lung cancers harbouring these genome changes can potentially be treated with agents approved for other indications or under clinical development. This review updates the therapeutic arsenal that especially targets those genes.

Targeting immune cell types of tumor microenvironment to overcome resistance to PD-1/PD-L1 blockade in lung cancer

“…The global lung cancer occurrence could be due to outdoor ambient PM2.5 and tobacco ( Guo et al, 2020 ; Turner et al, 2020 ; Frazer et al, 2022 ). Multiple gene mutations have been found in NSCLC patient, including epidermal growth factor receptor (EGFR) ( Zhao D. et al, 2022 ; Castaneda-Gonzalez et al, 2022 ), Kirsten rat sarcoma viral oncogene homolog (KRAS) ( Desage et al, 2022 ; Garcia-Robledo et al, 2022 ), anaplastic lymphoma kinase (ALK) ( Cognigni et al, 2022 ; Xiang et al, 2022 ), Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2) ( Ni and Zhang, 2021 ; Vathiotis et al, 2021 ; Yu X. et al, 2022 ), B-Raf proto-oncogene (BRAF) ( Abdayem and Planchard, 2022 ; Riudavets et al, 2022 ; Sforza et al, 2022 ), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT serine/threonine kinase 1 (AKT1), mitogen-activated protein kinase kinase 1 (MAP2K1) ( Kim and Giaccone, 2018 ; Han et al, 2021 ), c-ros oncogene 1 (ROS1) ( Guaitoli et al, 2021 ; Yu Z. Q. et al, 2022 ), neurotrophic tyrosine receptor kinase (NTRK) ( Liu C. et al, 2022 ; Qin and Patel, 2022 ), and mesenchymal-epithelial transition factor (MET) ( Pao and Girard, 2011 ; Olmedo et al, 2022 ) ( Figure 1 ). In SCLC patients, gene mutations often include retinoblastoma (Rb), TP53, PTEN, FBXW7, VHL mutations ( Cardona et al, 2019 ; Guan et al, 2022 ).…”

A comprehensive overview of the relationship between RET gene and tumor occurrence

“…Rearranged during transfection (RET) was first identified in 1985 in the transfection of NIH3T3 ( 1 ). RET gene has been confirmed to have a great role in the development of the kidney and nervous systems ( 2 ). The mechanism of RET aberrant activation was different from that of other receptor tyrosine kinases, which need both additional glial cell-derived neurotrophic factor (GDNF) family receptor-α (GFRα) and co-receptors (GFα1/2/3/4).…”