KRAS Mutations in Lung Adenocarcinoma: Molecular and Epidemiological Characteristics, Methods for Detection, and Therapeutic Strategy Perspectives

Abstract

KRAS mutations are detected in over one third of lung adenocarcinomas, most frequently in Caucasian and smoker patients. The impact of KRAS mutations on lung adenocarcinoma prognosis is currently subject to debate, as is their impact on the response to chemotherapy and EGFR tyrosine kinase inhibitors. The different methods for KRAS status assessment, based on histological and cytological samples or biological fluids, offer varying sensitivities. Since no treatments are available in clinical routine for KRAS-mutated lung cancer patients, one of the current major challenges in thoracic oncology is developing new dedicated strategic therapies. Different molecules can be developed that act on a post-transcriptional KRAS protein level, blocking its cytoplasmic membrane recruitment. The efficacy of these molecules' targeting of the different signaling pathways activated by the KRAS mutation (such as the MEK and BRAF pathways) is related to the particular KRAS mutation subtype. New therapeutic strategies are currently focused on certain genes linked with KRAS inducing a synthetic lethal interaction. The purpose of this work is to provide an overview of i) the recent epidemiological and molecular findings concerning KRASmutated lung adenocarcinoma, ii) the prognostic impact of KRAS mutations, in particular during response to treatment, iii) the available methods for detecting this mutation, and iv) the current molecules under development for new therapeutic strategies and the clinical trials targeting this genomic alteration.

EGFR and KRAS Mutations Predict the Incidence and Outcome of Brain Metastases in Non-Small Cell Lung Cancer

“…The frequency of KRAS -mutant (34%) and EGFR -mutant (12.5%) tumors was indeed similar that observed in other Caucasian populations of advanced NSCLC patients [20,21]. Furthermore, we analyzed data not only from patients enrolled in clinical trials, but also from all patients diagnosed in routine practice.…”

Mutations in KRAS codon 12 predict poor survival in Chinese patients with metastatic colorectal cancer

“…For example, Bournet et al (31) reported that KRAS G12D mutant was an independent prognostic factor for unresectable pancreatic cancer. It had been proposed that in non-small cell lung cancer, the G12D mutation subtype was associated with the activation of the phosphoinositide 3-kinase/AKT serine/threonine kinase (AKT) and MEK signaling whereas mutation G12V or G12C preferred to activate Raf and Ral, and decreased growth factor-dependent AKT activation (32,33). These findings led to the present study in which the association between signaling pathways and the role of KRAS mutation subtypes on prognosis of patients with CRC were investigated, particularly in patients with mCRC from different regions.…”

Evaluation of a fast and fully automated platform to diagnoseEGFRandKRASmutations in formalin-fixed and paraffin-embedded non-small cell lung cancer samples in less than one day

“…Other genetic alterations are promising molecular targets as ROS1 or RET rearrangements or BRAF , PIK3CA, C-MET and HER2 mutations 4–8. Other biomarkers as KRAS mutations are associated with a poor prognosis but do not allow targeted therapies to date with nevertheless some recent encouraging results in this field 9 10. Driver genetics alterations are mostly mutually exclusive and, besides EGFR and ALK testing recommended in international guidelines, a rapid KRAS assay may be performed initially as a help to exclude KRAS -mutated tumours from EGFR mutation testing as a part of an algorithm designed to maximise testing efficiency 11 12…”