Targeting KRAS Mutant Non-Small-Cell Lung Cancer: Past, Present and Future

Abstract

Lung cancer is the most frequent cancer with an aggressive clinical course and high mortality rates. Most cases are diagnosed at advanced stages when treatment options are limited and the efficacy of chemotherapy is poor. The disease has a complex and heterogeneous background with non-small-cell lung cancer (NSCLC) accounting for 85% of patients and lung adenocarcinoma being the most common histological subtype. Almost 30% of adenocarcinomas of the lung are driven by an activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. The ability to inhibit the oncogenic KRAS has been the holy grail of cancer research and the search for inhibitors is immensely ongoing as KRAS-mutated tumors are among the most aggressive and refractory to treatment. Therapeutic strategies tailored for KRAS+ NSCLC rely on the blockage of KRAS functional output, cellular dependencies, metabolic features, KRAS membrane associations, direct targeting of KRAS and immunotherapy. In this review, we provide an update on the most recent advances in anti-KRAS therapy for lung tumors with mechanistic insights into biological diversity and potential clinical implications.

AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer

“…Interestingly, in that model, Ago2 ablation had no effect on PDAC progression in the setting of p53 loss (13). Taken together, these findings suggest AGO2 inhibition might be applied to target multiple forms of KRAS-driven cancer with different downstream effector pathways (44). Based on this potential pharmacologic flexibility, the AGO2-KRAS interaction warrants further study in NSCLC and other KRAS-driven malignancies.…”

“…The clinical relevance of aberrant RAS signaling in this and other cancer types has prompted a long-standing search for effective RAS inhibitors that has been hampered by structural and biochemical features of the RAS molecule (8,9). Attempts to block downstream effectors, disrupt RAS subcellular localization, and identify synthetic lethal partners have also met with only limited clinical success (44). In this setting, the search for KRAS interaction partners represents an alternate approach for identifying new drug targets.…”

Melatonin Downregulates PD-L1 Expression and Modulates Tumor Immunity in KRAS-Mutant Non-Small Cell Lung Cancer

“…NSCLC patients with a KRAS mutation show a poor response to front-line chemotherapy, and they often exhibit worse prognoses. Disappointingly, unlike other oncoproteins, the mutant KRAS protein is thought to be an undruggable target due to various conformations of its mutant types [ 2 , 3 ]. Recently, immune checkpoint blockage through targeting programmed death-ligand 1 (PD-L1) and by its receptor programmed death-1 (PD-1), has changed the treatment paradigm for lung cancer patients, especially for those harboring a KRAS mutation [ 4 ].…”

Transcriptomic heterogeneity of driver gene mutations reveals novel mutual exclusivity and improves exploration of functional associations

“…In this research, there were three mutually exclusive triples that independently predicted shorter survival of LUAD patients than the wild-type samples, namely "TP53 subtype one-KRAS subtype three-FAM47C subtype two," "KEAP1 subtype two-FAT3 subtype one -EGFR subtype one," and "TP53 subtype one-MUC16 subtype one-KRAS subtype three." Although, TP53 mutations, 84,85 KRAS mutations, 86,87 and KEAP1 mutations 88 were predictive of survival of lung cancer patients. This result revealed that mutually exclusive triples could serve as biomarkers of LUAD patients or therapeutic targets.…”