No abstract

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Non-small cell lung cancer (NSCLC), comprising 85% of lung cancer cases, has been associated with resistance to chemo/radiotherapy. The hypoxic tumor micro-environment, where insufficient vasculature results in poor drug penetrance and sub-optimal chemotherapy in the tumor interiors contributes heavily to this resistance. Additionally, epigenetic changes in tumorigenic cells also change their response to different forms of therapy. In our study, we have investigated the effectiveness of a combination of cisplatin with scriptaid [a pan-Histone Deacetylase inhibitor (HDACi)] in a model that mimics the tumor microenvironment of hypoxia and sub-lethal chemotherapy. Scriptaid synergistically increases the efficacy of cisplatin in normoxia as well as hypoxia, accompanied with reduced metastasis and enhanced DNA damage. Addition of scriptaid also overcomes the cisplatin resistance exhibited in lung cancer cells with stabilized hypoxia inducible factor 1 (HIF1)-α (mutant) and mutant p53. Molecular studies showed that the combination treatment increased apoptotic cell death in both normoxia and hypoxia with a dual role of p38MAPK. Together, our results suggest that the combination of low dose cisplatin and scriptaid is cytotoxic to NSCLC lines, can overcome hypoxia induced resistance and mutant p53- induced instability often associated with this cancer, and has the potential to be an effective therapeutic modality.

Objective: Receptor tyrosine kinases (RTK) are relevant therapeutic targets in the treatment of lung cancer. Germline susceptibility variants that influence these RTKs may provide new insights into their regulation. rs9387478 is located in the genomic interval between two RTK-genes ROS1/DCBLD1, of which ROS1 alterations are implicated in lung carcinogenesis and treatment response while the latter remains poorly understood. Materials and methods: Venous blood was drawn from 100 control and 231 case subjects. Genotype was scored by restriction fragment length polymorphism (RFLP), PCR amplification followed by HindIII digestion. Logistic regression was applied to compare the association between variables. Survival curve was plotted to draw a correlation between the genotype and overall survival. Also, eQTL and chromatin state changes were analyzed and correlated with the survival of patients using available datasets. Results: In our population smoking correlated significantly with lung cancer [OR= 2.607] with the presence of the minor allele ‘A’ enhancing the nicotine dependence [CA (OR=3.23)]. Individuals with homozygous risk allele ‘A’ had a higher chance of developing lung cancer [OR=2.65] than individuals with CA/CC implying a recessive model of association. Patients with CC/CA genotype had better overall survival than patients with AA genotype [161 days/142 days vs 54 days, p=0.005]. The homozygous risk allele was significantly associated with increased DCBLD1 and ROS1 expression in lung cancer, with enriched active histone marks due to the polymorphism. Interestingly, increased DCBLD1 expression was associated with poor outcomes in lung cancer. Conclusion: Overall, our study provides strong evidence that rs9387478 is significantly associated with both nicotine dependence and lung cancer in our North Indian cohort. The association of the SNP with prognostic genes, DCBLD1 and ROS1 make rs9387478 a promising prognostic marker in the North Indian population. The results obtained are significant, however, the study needs to be performed in a larger sample size.