Understanding the feasibility of chemotherapeutic and immunotherapeutic targets against non-small cell lung cancers: an update of resistant responses and recent combinatorial therapies

Abstract

Despite consistent progress in prompt diagnosis and curative therapies in the last decade, lung cancer (LC) continues to threaten mankind, accounting for nearly twice the casualties compared to prostate, breast, and other cancers. Statistics associate ~25% of 2021 cancer-related deaths with LC, more than 80% of which are explicitly caused by tobacco smoking. Prevailing as small and non-small cell pathologies, with respective occurring frequency of nearly 15% and 80–85%, non-small cell LCs (NSCLCs) are prominently distinguished into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), subtypes. Since the first use of epidermal growth factor receptor (EGFR) inhibitor gefitinib for NSCLC treatment in 2002, immense progress has been made for targeted therapies with the next generation of drugs spanning across the chronological generations of small molecule inhibitors. The last two years have overseen the clinical approval of more than 10 therapeutic agents as first-line NSCLC medications. However, uncertain mutational aberrations as well as systemic resistant responses, and abysmal overall survival curtail the combating efficacies. Of late, immune checkpoint inhibitors (ICIs) against various molecules including programmed cell death-1 (PD-1) and its ligand (PD-L1) have been demonstrated as reliable LC treatment targets. Keeping these aspects in mind, this review article discusses the success of NSCLC chemo and immunotherapies with their characteristic effectiveness and future perspectives.

Abstract

Graphical abstract.

Quantitative diversity of gene mutations manifesting NSCLC pathogenic manifestation. RET: rearrangements during transfection; MET: mesenchymal-epithelial transition; ROS1: Proto-oncogene tyrosine-protein kinase; NTRK1: neurotrophic tropomyosin receptor kinase 1; PI3K: phosphatidylinositol 3-kinase; RAS: rat sarcoma; BRAF: v-RAF murine sarcoma viral oncogene homolog B1; ALK: anaplastic lymphoma kinase; HER: human EGFR; CTLA-4: cytotoxic T-lymphocyte-associated antigen 4; IL-1α: interleukin-1α