Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives

Abstract

In the past few decades, several gene mutations, including the anaplastic lymphoma kinase, epidermal growth factor receptor, ROS proto-oncogene 1 and rat sarcoma viral oncogene homolog (RAS), have been discovered in non-small cell lung cancer (NSCLC). Kirsten rat sarcoma viral oncogene homolog (KRAS) is the isoform most frequently altered in RAS-mutated NSCLC cases. Due to the structural and biochemical characteristics of the KRAS protein, effective approaches to treating KRAS-mutant NSCLC still remain elusive. Extensive recent research on KRAS-mutant inhibitors has made a breakthrough in identifying the covalent KRASG12C inhibitor as an effective agent for the treatment of NSCLC. This review mainly concentrated on introducing new covalent KRASG12C inhibitors like sotorasib (AMG 510) and adagrasib (MRTX 849); summarizing inhibitors targeting the KRAS-related upstream and downstream effectors in RAF/MEK/ERK pathway and PI3K/AKT/mTOR pathway; exploring the efficacy of immunotherapy and certain emerging immune-related therapeutics such as adoptive cell therapy and cancer vaccines. These inhibitors are being investigated in clinical trials and have exhibited promising effects. On the other hand, naturally extracted compounds, which have exhibited safe and effective properties in treating KRAS-mutant NSCLC through suppressing the MAPK and PI3K/AKT/mTOR signaling pathways, as well as through decreasing PD-L1 expression in preclinical studies, could be expected to enter into clinical studies. Finally, in order to confront the matter of drug resistance, the ongoing clinical trials in combination treatment strategies were summarized herein.

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

“…KRAS mutations are associated with treatment efficacy and prognosis in NSCLC ( Wood et al, 2016 ; Ferrer et al, 2018 ; Roman et al, 2018 ). Targeting KRAS variant has be shown to have potential treatment applications in NSCLC ( Ricciuti et al, 2016 ; Uras et al, 2020 ; Li J. X. et al, 2022 ). Notably, KRAS mutations are linked to immune therapy resistance in NSCLC patients ( Kim et al, 2017 ; Adderley et al, 2019 ).…”

The Oxidative Drug Combination for Suppressing KRAS G12D Inducible Tumour Growth

“…KRAS, a member of the RAS family of protooncogenes, has been associated with a range of high-grade malignancies. KRAS has been identified as the most frequently mutated gene in human cancers that is responsible for 30% of all human carcinomas [1][2][3][4]. Studies found that the mutant version of KRAS was presented in 90% of pancreatic cancers [5][6][7], and up to 40% of colorectal cancers [3].…”