Abstract 2688: The HSP90 inhibitor, onalespib (AT13387), delays the emergence of resistance to erlotinib in an EGFR-driven xenograft model
Authors: Courtin Aurélie , Smyth Tomoko , Hearn Keisha , Lyons John , Thompson Neil , Wallis Nicola G. 
Published: August 2015

Abstract
Background: Kinase inhibitors have been used successfully in the clinic, but relapse is common due to the emergence of resistance. Inhibition of HSP90 leads to the depletion of oncogenic ‘client’ proteins and the simultaneous inhibition of many signalling pathways. As such, the use of HSP90 inhibitors to overcome resistance has been widely investigated. Onalespib (AT13387) is a potent, second generation HSP90 inhibitor, which has been studied in many preclinical models of kinase inhibitor resistance. Recent findings indicate that an upfront combination of onalespib and either vemurafenib or crizotinib, in models of mutant BRAF melanoma or ALK-translocated non-small cell lung cancer (NSCLC), can delay the emergence of resistance to these therapies. Here we have extended this work to a combination of onalespib and erlotinib in an EGFR-driven NSCLC model.
Methods: Mice bearing HCC827 tumor xenografts were dosed with either 12.5 mg/kg erlotinib po qd, or a combination of 12.5 mg/kg erlotinib and 55 mg/kg onalespib ip qw for 52 weeks.
Results: Initially both the erlotinib single-agent and onalespib/erlotinib combination treatments significantly inhibited tumor growth of the EGFR-driven NSCLC HCC827 xenograft model; all tumors in the monotherapy and combination groups regressed rapidly and achieved complete response (CR) (median times to CR were 79 and 56 days for monotherapy and combination treatments respectively). However, after 20 weeks of continuous treatment, tumor relapse was observed in one of the xenografts dosed with erlotinib only and this was followed by regrowth of a further 2 tumors in this group over the 52-week study period, with these tumors reaching 50% of the original tumor volumes by 26 and 46 weeks. Of the remaining tumors, 5 out of 6 were detectable at the end of the study. In comparison, tumor growth remained inhibited in the group treated with the erlotinib/onalespib combination; no tumors were observed to regrow over the course of the study and none (of 9) were palpable when treatments were terminated. This suggests that while treatment with monotherapy erlotinib in this model leads to relapse, as seen in the clinic, combination treatment with onalespib can delay the emergence of resistance.
Conclusions: These data demonstrate that an upfront combination of onalespib and erlotinib can delay the emergence of resistance in an EGFR-driven xenograft model, suggesting there is therapeutic potential for an upfront erlotinib/onalespib combination in the clinic. Onalespib is currently being tested in a Phase 2 clinical trial in combination with crizotinib in ALK-positive NSCLC. The preclinical data presented here, alongside our previous data on combinations of onalespib with vemurafenib or crizotinib, suggest that the concept of using an HSP90 inhibitor combination upfront in the clinic to delay resistance could be extended to further targeted therapies.
Citation Format: Aurélie Courtin, Tomoko Smyth, Keisha Hearn, John Lyons, Neil Thompson, Nicola G. Wallis. The HSP90 inhibitor, onalespib (AT13387), delays the emergence of resistance to erlotinib in an EGFR-driven xenograft model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2688. doi:10.1158/1538-7445.AM2015-2688