Abstract 2166: Rapamycin can overcome ABT-737 resistance in patient-derived SCLC xenograft models.
Authors: Connis Nick , Gardner Eric E. , Poirier John T. , Kamat Chandrashekhar D. , Cope Leslie , Rudin Charles M. , Hann Christine L. 
Published: August 2014

Small cell lung cancer (SCLC) is an aggressive form of lung cancer with one of the highest case fatality rates among cancers. Standard therapy for SCLC has not changed in nearly 30 years and despite high initial response rates, treatment-refractory recurrence is nearly universal. Overexpression of the anti-apoptotic protein, Bcl-2, is observed in the majority of SCLC cases and is associated with therapy resistance. We have previously shown that the small molecule BH3 mimetic, ABT-737, is cytotoxic against Bcl-2 expressing SCLC cell lines in vitro and causes dramatic tumor regressions in SCLC cell line-based xenografts in vivo (Hann et al., Can Res 2008). We have also assessed the activity of ABT-737 in patient-derived (PD) SCLC xenografts; a model we believe better reflects patient tumor biology (Daniel et al., Can Res 2009). In PD SCLC xenografts that express high levels of Bcl-2, we found that treatment with ABT-737 caused tumor growth inhibition (TGI) but without any regressions. Our results in PD xenografts mirrored the activity seen clinically with ABT-263, an orally bioavailable form of ABT-737. In early phase trials, ABT-263 had limited single-agent activity in patients with recurrent SCLC (Rudin et al., Clin Can Res 2012).

To identify factors that contribute to ABT-737 resistance we compared the gene expression profiles of PD SCLC xenografts after treatment with ABT-737 to treatment-naïve tumors. We then used the Connectivity Map database to identify compounds that could potentially overcome ABT-737 resistance by inducing gene expression changes inverse to those observed in ABT-737 resistant xenografts. The top candidates from our query included inhibitors of the PI3K/mTOR axis. mTOR plays a key role in the hypoxic response through positive regulation of HIF1α and its downstream targets; this pathway was one of the most enriched gene expression profiles in our ABT-737 resistant xenografts.

We assessed the combination of ABT-737 and the mTOR inhibitor, rapamycin, in two PD SCLC xenografts. We found that combination treatment was well-tolerated and resulted in rapid tumor regression in mice. This response was durable; after treatment discontinuation, the combination-treated tumors remained too small to measure for over 30 days. In contrast, treatment with either ABT-737 or rapamycin alone caused TGI but no tumor regressions. Furthermore, combination treatment of animals that had previously received either single agent also resulted in tumor regression, suggesting that resistance to combination therapy did not develop after exposure to either single agent in the acute setting. Correlative studies of the mTOR and HIF1α pathways on our models and efficacy studies in additional PD SCLC xenografts are currently underway. As the safety of ABT-263 has been determined in early phase clinical trials and several FDA-approved mTOR inhibitors are currently available, this treatment paradigm may have clinical applicability.

Citation Format: Nick Connis, Eric E. Gardner, John T. Poirier, Chandrashekhar D. Kamat, Leslie Cope, Charles M. Rudin, Christine L. Hann. Rapamycin can overcome ABT-737 resistance in patient-derived SCLC xenograft 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 2166. doi:10.1158/1538-7445.AM2013-2166