Targeting the KRAS variant for treatment of non-small cell lung cancer: potential therapeutic applications

Abstract

Lung cancer is the leading cause of cancer deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 80% of all lung cancers. Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the deadliest cancer-related proteins and plays a pivotal role in the most aggressive and lethal human cancers, including lung adenocarcinoma where it represents one of the most frequently mutated oncogene. Although therapeutic progresses have made an impact over the last decade, median survival for patients with advanced lung cancer remains disappointing, with a 5-year worldwide survival rate of <15%. For more than 20 years it has been recognized that constitutively active signaling downstream of KRAS is a fundamental driver of lung tumorigenesis. However, years of pursuit have failed to yield a drug that can safely curb KRAS activity; up to now no approved therapies exist for KRAS-mutant NSCLC. The aim of this review is to discuss the current knowledge of KRAS-mutated NSCLC, touching upon KRAS clinical relevance as a prognostic and predictive biomarker, with an emphasis on novel therapeutic approaches for the treatment of KRAS-variant NSCLC.

KRAS mutation and DNA repair and synthesis genes in non‑small‑cell lung cancer

“…advanced NSCLCs, which would be of clinical relevance owing to the fact that KRAS mutation are mainly found in adenocarcinoma patients, and pemetrexed is approved for clinical use in this histological subset only (4,11). Previously, Moran and colleagues have already reported that KRAS-mutant cell line depend on enhanced folate metabolism in functional experiments (12).…”

“…Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation represents the most common genetic alteration in NSCLC, being found in approximately 20-30% of patients (4). Although KRAS acts as a driver mutation in NSCLC, it is not yet an actionable target, since clinical trials with targeted therapies aimed at blocking the RAS pathway have invariably led to disappointing results.…”

CDKN1A upregulation and cisplatin‑pemetrexed resistance in non‑small cell lung cancer cells

“…In addition to epidermal growth factor receptor (EGFR) mutations that occur in approximately 50% of patients, the oncogene KRAS, responsible for tumor formation, and the tumor suppressor gene TP53, implicated in cell cycle regulation, cell proliferation and apoptosis, are also frequently mutated in this type of tumor, with EGFR and KRAS mutations generally mutually exclusive (1). The role of such mutations in the selection of the anticancer treatment is still under debate, even though it appears that they may be associated with differential sensitivity patterns to currently available therapies (5,6).…”

Treating KRAS-mutant NSCLC: latest evidence and clinical consequences

“…It is more common in western (26%) than in Asian (11%) populations and in smokers (30%) than nonsmokers (10%). 6 The smoking pattern has also been related to the type of KRAS mutation; transversion mutations (substitution of a purine nucleotide to a pyrimidine or vice versa) are more common in current or ex-smoker patients while never-smoker NSCLC patients have a higher frequency of transition mutations (purine to purine or pyrimidine to pyrimidine nucleotide changes). 7 , 8 …”