Abstract 5279: HSP72 expression and suppression of resistance is associated with survival in <i>EGFR</i> mutated NSCLC
Authors: Li Zheng, Angel R. Baroz, Erminia Massarelli, Joy Huang, Ravi Salgia, Binghui Shen, Karen L. Reckamp
Journal: Cancer Research (2020)

Abstract Background: Patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations initially respond favorably to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Acquired resistance develops in most patients, usually due to new DNA mutations. Our previous work has shown that EGFR-TKI therapy blocked phosphorylation of Hsp72, leading to degradation and suppression of polymerase α error editing and base excision repair, causing an increase in the overall mutation rate. This study evaluated baseline Hsp72 expression in EGFR mutated NSCLC and assessed Hsp72 ability to suppress EGFR-TKI resistance and improve overall survival (OS) of patients with EGFR mutated NSCLC. Methods: A retrospective cohort of patients was identified with known EGFR mutation positive NSCLC and available tissue from the City of Hope Comprehensive Cancer Center seen between 2008 and 2016. Patients were classified into two groups based on HSP72 levels: less than the mean HSP72 level (low expression, n = 40) and greater than or equal to the mean HSP72 level (high expression, n = 22), and examined OS. A chi-square test for categorical data and multivariate logistic regression analyses was used to study the relation between HSP72 expression and other clinical and demographic data. In vitro, HSP72 overexpression was induced by BPG-15 and degradation was blocked with bortezomib. We analyzed resistance in EGFR mutant NSCLC with osimertinib alone, and in combination with osimertinib and BPG-15 or bortezomib. Results: Sixty-three patients with EGFR mutated NSCLC and available tissue were identified. Median survival of high and low HSP72 expression were 51.5 and 28.8 months respectively (p = 0.003, log-rank test), with HR of 0.47 (95% CI 0.29-0.77). When stratifying by stage (removal of stage I and II patients), the HR associated with a high HSP72 expression remained 0.47 (95% CI 0.29-0.77). In vitro studies showed that in the absence of bortezomib or BGP-15, time to resistance to osimertinib in HCC827 cells was 13 days. In the presence of bortezomib or BGP-15, time to resistance was 29 and 25 days, respectively. A similar phenomenon was observed with the EGFR-TKI, erlotinib. Conclusions: In EGFR mutated NSCLC, a high level of HSP72 expression is associated with improved survival. Furthermore, HSP72 inducing drugs delays the development of resistance in EGFR-mutated NSCLC cancer cells, and mechanisms are under investigation. Supported by R01 CA073764 (BHS), R50 CA211397 (LZ), the William and Anna Tenenblatt Foundation (BHS, KR) and the STOP Cancer Carrie Scott Seed grant (KR). Citation Format: Li Zheng, Angel R. Baroz, Erminia Massarelli, Joy Huang, Ravi Salgia, Binghui Shen, Karen L. Reckamp. HSP72 expression and suppression of resistance is associated with survival in EGFR mutated NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5279.