Abstract 1735: Identification of novel synthetic lethal interactions in small cell lung cancer with the proteasome inhibitor carfilzomib

Proteasome inhibition (PI) has emerged as a valuable cancer treatment in hematological malignancies by causing a disruption of protein homeostasis. While proteasome inhibitors have been historically unsuccessful in the clinic for solid tumors, all cancer cell lines succumb to proteasome inhibition in vitro. Solid tumor cell lines have a higher threshold for disruption of protein homeostasis; as they require continuous exposure to achieve cytotoxicity similar to pulsatile exposure of PI in heme cell lines. The in-vivo half-life of proteasome inhibitors is short (∼1hr) making it challenging to mimic in vitro continuous treatment. Therefore we explored the option of sensitizing solid tumors to proteasome inhibitors through combination therapy.In order to identify novel synthetic lethal interactions with PI, we performed a screen utilizing a pooled siRNA library targeting 2240 genes of the druggable genome in combination with the proteasome inhibitor carfilzomib (CFZ) or DMSO. Cells were first transfected with the siRNA for 24 hours and then treated with CFZ or DMSO for an additional 72h to assess synergy. We performed the screen in small cell lung cancer (SCLC), an unmet medical need. Preliminary responses in SCLC patients were observed with CFZ in an all comers solid tumor trial (Papadopoulos, et al. Cancer Chemother Pharmacol, 2013).The screen was performed in NCI-H841 cells that are adherent, easy to culture, and have high transfection efficiency. The combined effect of siR...

Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Masto, V. B., Lerner, A. G., Arastu-Kapur, S. Tags: Experimental and Molecular Therapeutics Source Type: research