PMC:4706832 / 1380-5418 JSONTXT

{"project":"2_test","denotations":[{"id":"28330089-22237781-393","span":{"begin":128,"end":132},"obj":"22237781"},{"id":"28330089-18097461-394","span":{"begin":985,"end":989},"obj":"18097461"},{"id":"28330089-20979473-395","span":{"begin":1697,"end":1701},"obj":"20979473"},{"id":"28330089-21288922-396","span":{"begin":1885,"end":1889},"obj":"21288922"},{"id":"28330089-19667264-397","span":{"begin":2030,"end":2034},"obj":"19667264"},{"id":"28330089-23344087-398","span":{"begin":3002,"end":3006},"obj":"23344087"},{"id":"28330089-22235099-399","span":{"begin":3161,"end":3165},"obj":"22235099"},{"id":"28330089-18452692-400","span":{"begin":3181,"end":3185},"obj":"18452692"}],"text":"Introduction\nLung cancer is the prominent cause of cancer deaths in the world and a global issue to be addressed (Siegel et al. 2012). Lung cancer is broadly classified into two main types based upon their histology, which are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The most common forms of NSCLC are adenocarcinoma (ADC) and squamous cell carcinoma (SCC) (Skarda et al. 2008). Chromosomal rearrangements in the anaplastic lymphoma kinase (ALK) gene that codes for anaplastic lymphoma kinase has been identified as one of the causes of NSCLC. There are two types of tyrosine kinase, receptor and cytoplasmic tyrosine kinase. The ALK is a cytoplasmic tyrosine kinase where crizotinib (a potential anticancer drug used in the treatment of NSCLC) is bound. Chromosomal rearrangements involving the ALK gene occur in different malignant conditions, including anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT) (Chiarle et al. 2008). These rearrangements lead to the expression of ALK fusion genes. ALK fusion gene possesses different properties from the two genes that it was originally derived from, can then code for the new ALK fusion protein, which is abnormally and constitutively activated. The new protein contains the tyrosine kinase domain of ALK and the coiled coil domain of EML4. The coiled coil domain of EML4 allows this protein to bind with other ALK fusion proteins and form dimerised and activated fusion proteins (Katayama et al. 2012). The most prevalent ALK fusion oncogene in NSCLC is the echinoderm microtubule-associated protein-like 4 (EML4)–ALK fusion gene and is present in 4–5 % of cases of NSCLC (Young et al. 2010). An inversion in the chromosome 2 brings together the 5′ end of the EML4 gene and the 3′ end of the ALK gene resulting in the formation of the EML4-ALK fusion gene (Shaw and Solomon 2011). The affected person tend to have typical clinical features like early age of onset, little or absence of any smoking history (Shaw et al. 2009). Some of the drugs commonly used for the chemotherapeutic treatment of lung cancer are Bevacizumab, Carboplatin, Cisplatin, Crizotinib, Docetaxel, Erlotinib, Etoposide, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, and Vinorelbine. Targeted drug therapy is used against NSCLC of which tyrosine kinase inhibitors are amongst the best method in treatment methodology. In particular, crizotinib is one such tyrosine kinase inhibitor which is the first drug to have gained FDA approval for the treatment of NSCLC in 2011 (Ou, 2011). Although crizotinib has proved itself as an efficient counter to ALK type NSCLC, acquired resistance has made its beneficial effects temporary and has emerged as a major roadblock for crizotinib. The literature evidences available indicates that L1196M (the “gatekeeper” mutation) and G1269A are the two most commonly found secondary mutations in the ALK kinase domain. In a few cases, patient harbored with both mutation (Kim et al. 2013). Of note, the available evidence indicates that ALK double mutation (L1196M, G1269A) is one of the main causes for crizotinib resistance (Doebele et al. 2012; Molina et al. 2008). The prevalence of ALK double mutation (L1196M, G1269A) is also significantly higher than other mutation. These situations urge the development of new and more effective ALK inhibitors especially for the treatment of drug resistance NSCLC. For years, computational techniques in particular virtual screening (VS) have proven to be of great use to make the drug development process faster and less expensive. The available literature evidences also suggested that VS techniques proved to be efficacious in making qualitative predictions that discriminated active from inactive compounds (Oprea 2000; Chen 2008). Therefore, in the present investigation, we have employed VS technique to address the crizotinib resistance in NSCLC. We hope that this approach certainly helpful for the experimental biologist to figure out the potent candidates for NSCLC."}