Development of Specific Inhibitors that Prevent hnRNPA1-Mediated Therapy Resistance in Small Cell Lung Cancer.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a diverse family of RNA-binding proteins (RBPs) that are involved in many steps in gene regulation. The hnRNP family consist of 20 members which are expressed in humans (A1 to U). The first member identified being hnRNP A1; this is a multipurpose protein involved in RNA processing. HnRNP A1 is abnormally expressed in Small cell lung cancer (SCLC); reducing hnRNP A1 in lung cancer cells inhibited cell growth and number of colonies, as well as arresting cells in the G0/G1 phase of the cell cycle. SCLC is extremely metastatic and aggressive; it is responsible for 13% of all lung cancer cases. Initially, SCLC responds very well to treatment, however, relapse usually occurs within a year. This indicates that SCLC cells have a multidrug resistance to therapies subsequently leading to poor prognosis. Fibroblast growth factor 2 (FGF-2) signalling leads to cell death resistance by providing cancerous cells with survival signals that leads to therapy resistance. FGF-2 signalling results in the activation of hnRNP A1 boosting the translation of anti-apoptotic proteins BCL-XL and XIAP. FGF-2 signalling is overactivated in SCLC cells. Finding a drug that binds to hnRNP A1 inhibiting its activation would be a successful SCLC therapy as the translation of anti-apoptotic proteins would be halted. In this study, I aim to identify ligands that bind successfully to the Nterminal of hnRNP A1 (UP1). These ligands can then be researched further becoming drug therapies for drug-resistant SCLC.