Background: Although Epidermal Growth Factor Receptor (EGFR)-driven non-small cell lung cancer (NSCLC) can be successfully treated with EGFR inhibitors such as erlotinib, relapse is common due to the development of resistance. Methods to improve response and delay resistance are therefore of value. Inhibition of the chaperone, HSP90, leads to the depletion of many client proteins, including EGFR, and has the capacity to simultaneously affect many signalling pathways, offering an alternative strategy for targeting EGFR-driven disease. AT13387 is a potent, second generation HSP90 inhibitor currently being tested in Phase II clinical trials. Here we investigated the effects of combining AT13387 and erlotinib in models of EGFR-driven NSCLC.

Results: AT13387 single-agent treatment was effective in EGFR-driven NSCLC xenograft models, significantly inhibiting tumor growth of both HCC827 and NCI-H1650 xenograft tumors when dosed once weekly (see table). As expected, treatment with erlotinib caused significant tumor regression in all HCC827 tumors, but was less effective in the NCI-H1650 model; its PTEN status conferring a reduction in sensitivity. However, combination of AT13387 with erlotinib led to a further enhancement of tumor growth inhibition over either of the monotherapies in both of these models. All HCC827 tumors treated with the combination regressed further (by at least 80%), and regression was also now observed in all NCI-H1650 tumors. These data demonstrate that combination with AT13387 has the potential to increase response, despite the differing initial sensitivities to erlotinib of these models. The combination was well tolerated.

Effects of AT13387 and erlotinib on EGFR-driven xenografts 
Cell line Genetic Background T/C(Median RTV, treated / control) 
  AT1338755 mg/kg ip 1qw Erlotinib12.5 mg/kg po qd Combination 
HCC827(Day 32) EGFR Del E746_A750 26% 17%(47% regression) 6%(84% regression) 
NCI-H1650(Day 31) EGFR Del E746_A750/PTEN del 35% 36% 6%(50% regression) 
Effects of AT13387 and erlotinib on EGFR-driven xenografts 
Cell line Genetic Background T/C(Median RTV, treated / control) 
  AT1338755 mg/kg ip 1qw Erlotinib12.5 mg/kg po qd Combination 
HCC827(Day 32) EGFR Del E746_A750 26% 17%(47% regression) 6%(84% regression) 
NCI-H1650(Day 31) EGFR Del E746_A750/PTEN del 35% 36% 6%(50% regression) 
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Conclusions: AT13387 was shown to improve response when combined with erlotinib in EGFR-driven xenograft models. These data suggest that there is therapeutic potential in an upfront combination of an HSP90 inhibitor, such as AT13387, with erlotinib and support clinical investigation of such a combination.

Citation Format: Tomoko Smyth, Jon Lewis, Keisha Hearn, Neil Thompson, John Lyons, Nicola G. Wallis. The HSP90 inhibitor, AT13387, combined with erlotinib improves response in EGFR-driven xenograft models of NSCLC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1794. doi:10.1158/1538-7445.AM2014-1794

©2014 American Association for Cancer Research.
2014