Molecular Biology and Therapeutic Perspectives for K-Ras Mutant Non-Small Cell Lung Cancers

Abstract

In non-small cell lung cancer (NSCLC) the most common alterations are identified in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, accounting for approximately 30% of cases in Caucasian patients. The majority of mutations are located in exon 2, with the c.34G > T (p.G12C) change being the most prevalent. The clinical relevance of KRAS mutations in NSCLC was not recognized until a few years ago. What is now emerging is a dual key role played by KRAS mutations in the management of NSCLC patients. First, recent data report that KRAS-mutant lung AC patients generally have poorer overall survival (OS). Second, a KRAS inhibitor specifically targeting the c.34G > T (p.G12C) variant, Sotorasib, has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency. Another KRAS inhibitor targeting c.34G > T (p.G12C), Adagrasib, is currently being reviewed by the FDA for accelerated approval. From the description of the biology of KRAS-mutant NSCLC, the present review will focus on the clinical aspects of KRAS mutations in NSCLC, in particular on the emerging efficacy data of Sotorasib and other KRAS inhibitors, including mechanisms of resistance. Finally, the interaction between KRAS mutations and immune checkpoint inhibitors will be discussed.

Genetic differences between smokers and never-smokers with lung cancer

“…When it is bound to GDP, it is inactive and does not relay signals to the cell’s nucleus. Gain-of-function KRAS mutations keep the protein permanently in its active state, leading to uncontrolled cell proliferation and cancerogenesis ( 34 , 59 , 61 , 62 ).…”

“…KRAS mutations were found in NSCLCs (predominantly adenocarcinomas), more frequently in smokers but not in small cell lung carcinomas ( 32 , 59 , 62 ). In more detail, the most common KRAS mutations, Gly12Cys and Gly12Val, are characteristic for smokers, while other mutations appear in never-smokers, suggesting different mechanisms of carcinogenesis ( 61 ). EGFR and KRAS mutations are mutually exclusive, i.e., generally, they were not observed in the same tumor ( 32 , 34 , 61 , 63 ).…”

“…In more detail, the most common KRAS mutations, Gly12Cys and Gly12Val, are characteristic for smokers, while other mutations appear in never-smokers, suggesting different mechanisms of carcinogenesis ( 61 ). EGFR and KRAS mutations are mutually exclusive, i.e., generally, they were not observed in the same tumor ( 32 , 34 , 61 , 63 ). This may be explained in two ways: First, EGFR and KRAS mutations happen preferentially in never-smokers and smokers, respectively, and therefore in different individuals.…”

“…However, the smoking status of these double-mutated cancers was not reported ( 33 , 34 , 64 ). KRAS mutations are usually not associated with mutations of other drivers of lung cancer development, ALK and ROS1 ; however, co-mutations of KRAS and other genes such as TP53 , STK11 , KEAP1 and NFE2L2 are more frequent ( 61 ).…”

Enhancing an Oxidative “Trojan Horse” Action of Vitamin C with Arsenic Trioxide for Effective Suppression of KRAS-Mutant Cancers: A Promising Path at the Bedside

“…KRAS is the most frequently mutated isoform among the RAS family of genes and is associated with an overall percentage of 75–83% of all RAS-mutated cancers, whereas NRAS is detected in only 8–17% and HRAS in 3–7% of all cases. Human pancreatic ductal adenocarcinomas (PDAC) carry the highest frequency of KRAS mutations (about 95%) whereas in colon and lung cancers it is approximately 50% and 35%, respectively [ 10 , 12 , 13 ]. A high KRAS mutation load is detected in other types of cancers, such as multiple myeloma, ovarian, uterine, and stomach cancers (22%, 15%, 18%, and 16%, respectively), whereas NRAS mutations are frequently detected in melanoma (30%), multiple myeloma (18%), acute myelogenous leukemia, colorectal cancer (CRC) (10%), and thyroid cancer (8%), and HRAS is the least frequently mutated RAS gene detected in cancers of the bladder, head, and neck squamous cell carcinomas and the uterus (5% or less) [ 12 ].…”