Abstract 1022: Carfilzomib demonstrates broad antitumor activity in preclinical lung cancer models.

Abstract

Abstract Carfilzomib (CFZ), is an irreversible inhibitor of the chymotrypsin-like activity of the proteasome that was recently FDA approved for treatment of refractory and relapsed multiple myeloma. Early Phase 1B studies of CFZ showed signs of clinical activity in a number of solid tumors, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). We investigated the anti-tumor activity of CFZ monotherapy and in combination with cisplatin in NSCLC and SCLC cell lines and xenograft models. CFZ showed marked anti-proliferative activity in A549, H1993, H520, H460, H1299 NSCLC cell lines, with IC50 values after 96 hours of treatment ranging from 1.0 nM to 27 nM. CFZ + cisplatin resulted in antagonistic anti-proliferative activity in the NSCLC A549, H1993, and H520 cells, independent of sequence of drug administration. In vivo, CFZ monotherapy resulted in tumor growth inhibition in an A549 NSCLC murine xenograft model. In contrast, the SCLC cell lines SHP77 and H69 were more resistant to the anti-proliferative effects of CFZ, with IC50 values at 96 hours of 0.917 μM and >30 μM, respectively. In vitro, in the SHP-77 SCLC cell line CFZ + Cisplatin showed synergistic activity. In vivo, in a SHP-77 SCLC SCID murine xenograft model CFZ monotherapy resulted in an 8-day tumor growth delay to reach 1500 mm3. No additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin in this model. Western blot analysis from SHP-77 cell lines grown in vitro and treated with CFZ showed an increase in cleaved PARP and p53, supporting activation of apoptosis. We will report on inhibition of the chymotrypsin-like proteasome activity in CFZ-treated lung cancer cell lines. Together, these pre-clinical studies support further preclinical and clinical investigations of CFZ in NSCLC and SCLC, including novel CFZ + anti-cancer drug combinations. Citation Format: Amanda F. Baker, Barbara Sands, Lilliana Carbajal, Janet Anderl, Elena T. Chan, Christopher J. Kirk, Linda L. Garland. Carfilzomib demonstrates broad antitumor activity in preclinical lung cancer models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1022. doi:10.1158/1538-7445.AM2013-1022