KRAS-Mutant non-small cell lung cancer: From biology to therapy

Abstract

In patients with non-small cell lung cancer (NSCLC), the most frequent oncogene driver mutation in Western countries is Kirsten rat sarcoma viral oncogene homolog (KRAS), and KRAS-mutant NSCLC is associated with smoking. There are various sources of biological heterogeneity of KRAS-mutant NSCLC, including different genotypes that may be associated with specific clinical outcomes, the presence of other co-mutations that exhibit different biological features and drug sensitivity patterns, and mutant allelic content. The efficacy of chemotherapy in patients with KRAS-mutant NSCLC is generally poor and numerous novel therapeutic strategies have been developed. These approaches include targeting KRAS membrane associations, targeting downstream signalling pathways, the use of KRAS synthetic lethality, direct targeting of KRAS, and immunotherapy. Of these, immunotherapy may be one of the most promising treatment approaches for patients with KRAS-mutant NSCLC. Recent data also suggest the potential for distinct efficacy of immunotherapy according to the presence of other co-mutations. In view of the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualised and, in future, may require the use of rational combinations of treatment, many of which are currently under investigation. 1. Introduction Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in approximately 20-25% of lung adenocarcinomas in Western countries [1-3] and in approximately 10-15% of cases in Asia [4,5]. Considered globally, KRAS-mutant tumours constitute the most frequent potentially targetable molecular subtype of non-small-cell lung cancer (NSCLC) [6]. As is the case with the vast majority of potentially

Elevation of CD109 promotes metastasis and drug resistance in lung cancer via activation of EGFR‐AKT‐mTOR signaling

“…NSCLC is comprised of squamous carcinomas, large cell carcinomas, and adenocarcinomas, and it accounts for nearly 85% of lung carcinomas 2 . Although chemotherapy and radiation therapy show responses during early treatment of NSCLC, molecular changes in NSCLC are a major problem that cause resistance and distant metastasis 3,4 . Therefore, understanding gene expression patterns and identifying underlying mechanisms will improve diagnoses and treatments for lung cancer.…”

Identifying relationships between imaging phenotypes and lung cancer-related mutation status: EGFR and KRAS

“…EGFR is over-expressed in 40 to 80% of NSCLC patients from never-smokers and it is associated with poor diagnosis 6,7 . Unlike the previous marker, KRAS is associated with tobacco use, with only 5 to 10% of KRAS-mutant lung cancers arising in never or light smokers 6,8 . Current molecularly-targeted therapies can effectively target specific biomarkers, decreasing multiple undesirable side effects associated with cancer treatment 9 .…”

The ACSL3-LPIAT1 signaling drives prostaglandin synthesis in non-small cell lung cancer

“…Non-small cell lung cancer (NSCLC) constitutes about 85% of all lung malignancies, out of which 30% harbor KRAS mutations that are associated with aggressive, therapy-resistant tumors [11]. KRAS upregulates COX2, and the latter produces prostaglandins, including prostaglandin E2 (PGE2), in order to promote tumor growth and metastasis [12].…”