Mechanisms and current advances in treating KRAS-mutated lung cancer

Lung cancer is the leading cause of cancer-related deaths, with the highest mortality among all cancers. Despite the significant advances in cancer treatments in recent years, especially with the development of checkpoint inhibitor immunotherapy, a definitive treatment has yet to be discovered to cure lung cancer. Lung tumorigenesis involves genetic alterations in a multi-step process with heterogeneity and diversity, such that even though cigarette smoke has been widely acknowledged as a major associated risk factor, many non-smokers still develop lung cancer. Among lung cancers, 85 % are non-small cell lung carcinoma (NSCLC), with adenocarcinoma as the most prevalent NSCLC subtype, making up around 40 % of all lung cancers. The major genetic mutation drivers include the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS). While the advancement of newer-generation anti-cancer drugs has successfully treated EGFR- and ALK-associated lung cancers, KRAS mutation-associated lung cancer remains extremely challenging and has limited therapeutic options. This review outlines the etiology, epidemiology, and categorization of lung cancer, describing the current therapeutic options and limitations, with a focus on the most challenging-to-treat KRAS-mutated lung cancer. Furthermore, this paper highlights the current state and development of KRAS-mutated cancer treatment by describing the mechanisms and utilities of various KRAS-targeted therapies entering clinical trials, and it underlines the most promising treatment options.