Many studies have showed that the Kras gene is activated by point mutations in approximately 15-20% of non-small cell lung cancers (NSCLCs), however, there are only a few reports on Nras mutations in NSCLC.
To the best of our knowledge, this is the largest single institution series to date evaluating racial differences in EGFR and KRAS mutational status among patients with NSCLC.
Despite these advances and recent studies on the predictive value of activating EGFR mutation and KRAS mutations with response in non-small-cell lung cancer and colon cancer patients, there is currently no reliable predictive marker for response to therapy with the anti-EGFR monoclonal antibodies cetuximab and panitumumab or the small molecule EGFR tyrosine kinase inhibitors gefitinib and erlotinib.
Tumor protein p53 gene (TP53) genomic alterations (GAs) were identified in 74% of cases, which had genomics distinct from TP53 wild-type cases, and 62% featured a GA in KRAS (34%) or one of seven genes currently recommended for testing in the National Comprehensive Cancer Network NSCLC guidelines, including the following: hepatocyte growth factor receptor gene (MET) (13.6%), EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%).
Because we found a higher frequency of EGFR/KRAS mutations in NSCLC cell lines with high PD-L1 expression (p < 0.001), we evaluated the relationships between downstream signals and PD-L1 expression, particularly in three KRAS-mutant adenocarcinoma cell lines.
Using a panel of 12 KRAS-mutated NSCLC models, we found that cell lines responsive to BET inhibitors underwent apoptosis and reduced their S-phase population, concomitant with downregulation of c-Myc expression.
In this study, we analyzed the expression of MAGE-A, a cancer-testis antigen, in tumors from a cohort of patients with resected NSCLC with respect to their clinicopathologic characteristics and their mutational status for the EGFR and KRAS genes.
After obtaining institutional review board approval, we enrolled patients (1) who had FDG PET/CT performed for staging of NSCLC, (2) with EGFR and KRAS mutational status of tumor identified, and (3) without uncontrolled diabetes.
CCND1 gene amplification and gene expression were analyzed in relation to mutational status of KRAS gene as well as to PTEN alterations (loss of heterozygosity and promoter hypermethylation) in NSCLC patient samples.
Recently, G12CKRAS mutation in isogenic NSCLC cell line has been shown to be a key player in promoting metabolic rewiring mainly through the regulation of glutamine metabolism to fuel growth and proliferation.
We selected NSCLC cell lines--A549 (KRASG12S), NCI-H3255 (EGFR L858R), NCI-H3122 (EML4-ALK E13;A20), and HCC78 (SLC34A2-ROS1)-to evaluate the antiproliferative effects of submicromolar concentrations of the multitargeted TKIs imatinib, sorafenib, erlotinib, and crizotinib.
This combination of the Wee1 inhibitor with sorafenib, if confirmed in models with different genetic backgrounds, might be worth investigating further as a new strategy for KRAS mutated NSCLC.
We performed a retrospective chart review of 513 patients with NSCLC undergoing EGFR and KRAS mutational analysis at the Hospital of the University of Pennsylvania between May 2008 and November 2011.
Isogenic pairs of KRAS-mutant NSCLC cell lines A549, H460 and H157, each with wild-type and null LKB1, as well as genetically engineered mouse-derived cell lines 634 (<i>kras</i><sup>G12D/wt</sup><i>/p53</i><sup>-/-</sup><i>/lkb1</i><sup>wt/wt</sup>) and t2 (<i>kras</i><sup>G12D/wt</sup><i>/p53</i><sup>-/-</sup>/<i>lkb1</i><sup>-/-</sup>) were used <i>in vitro</i> to analyze the activities of selumetinib, phenformin and their combination.
We further show in a phase II clinical trial in KRAS mutant advanced non-small cell lung cancer (NSCLC) with single agent sorafenib an improved disease control rate in patients using the antidiabetic drug metformin.
The mutation frequency of KRAS in NSCLC patients in mainland China is similar to those in East Asian countries, but lower than those in western countries.