Abstract 3887: Proteomic profiling identifies cMyc and TTF1 as biomarkers of response to the aurora kinase inhibitor alisertib in small cell lung cancer (SCLC)
Authors: Cardnell Robert J. , Li Lerong , Masrorpour Fatemeh , Niu Huifeng , Ecsedy Jeffrey , Wang Jing , Byers Lauren A. 
Published: July 2016

Background: Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, with a 5-year survival rate of only 6%. The treatment of SCLC has not changed in over 25 years, hence the development of new drugs for SCLC represents a major unmet need. A recent phase II trial of the aurora kinase inhibitor alisertib showed single agent activity in a subset (21%) of SCLC (Melichar et al, 2015) and a second study is underway testing alisertib in combination with chemotherapy (NCT02038647). However, there are currently no established biomarkers to identify patients likely to have the greatest benefit from alisertib. We have previously demonstrated the utility of proteomic profiling to identify targets and markers in SCLC. Here we use proteomics to identify markers of response to alisertib in SCLC.

Methods: The sensitivity (IC50) of 51 SCLC cell lines to alisertib was assayed in 5-day proliferation assays. Expression levels of 171 total and/or phosphorylated proteins were measured by reverse phase protein array (RPPA) and correlated with IC50’s. Using two approaches – 1) Spearman correlation of IC50 to protein data for all cell lines and 2) t-test comparing protein data between the most and least sensitive cell lines – we generated consensus markers of response.

Results: Proliferation assays showed sensitivity to alisertib at clinically achievable doses in 14/51 (27%) cell lines (based on Cmax = 1.8uM, Phase I single agent trial). High cMyc protein was the top marker of sensitivity to alisertib (R = -0.47, p = 0.0006 as continuous variables; fold difference = 3.52, p = 0.008 by t-test comparing extremes). Further analysis revealed a bi-modal distribution of cMyc protein, defined as high and low using a bimodality index. The cMyc protein high group (25%) included cell lines that were both cMyc amplified and non-amplified. While cMyc amplified cell lines (11%) are more sensitive to alisertib than non-amplified (p = 0.002), high cMyc protein captures a larger population of SCLC that is sensitive to alisertib.

In contrast, expression of thyroid transcription factor 1 (TTF1, a standard IHC marker used in the diagnosis of lung cancer) was the top marker of alisertib resistance (R = 0.38, p = 0.006; fold difference = -4.22, p = 0.003). TTF1 protein expression was also bi-modal, with 32% of cell lines falling into a distinct TTF1-low (more sensitive to alisertib) group.

Conclusions: High cMyc and low TTF1 protein expression identify a subset of SCLC cell lines (27%) that are sensitive to single agent alisertib. cMyc protein as a marker of response is consistent with other preclinical findings suggesting that cMyc amplified SCLC may be more sensitive to aurora kinase inhibition. The association of low TTF1 expression with alisertib sensitivity may prove to be of particular value in selecting patients for treatment given that immunohistochemical assessment of TTF1 is commonly used in the diagnosis of SCLC.

Citation Format: Robert J. Cardnell, Lerong Li, Fatemeh Masrorpour, Huifeng Niu, Jeffrey Ecsedy, Jing Wang, Lauren A. Byers. Proteomic profiling identifies cMyc and TTF1 as biomarkers of response to the aurora kinase inhibitor alisertib in small cell lung cancer (SCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3887.