Abstract 3623: Neoadjuvant chemotherapy is associated with increased expression of DNA repair proteins and epithelial to mesenchymal transition (EMT) in patients with non-small cell lung cancer (NSCLC)
Authors: Gomez Daniel R. , Diao Lixia , Wang Jing , Wistuba Ignacio I. , Moran Cesar , Kalhor Neda , Suraokar Milind B. , Swisher Stephen G. , Behrens Carmen , Fan Youhong , Heymach John V. , Byers Lauren A. 
Published: August 2015

Background: Proteomic profiling has elucidated several dysregulated pathways in NSCLC. We sought to identify patterns of protein expression that are enriched following neoadjuvant chemotherapy in patients with resected lung cancers.

Methods: Tissue samples were selected from the PROSPECT trial at MD Anderson Cancer Center, the goal of which was to correlate molecular profiles with treatment response. Samples from 189 patients were analyzed, which included 26% squamous tumors; 27% with neoadjuvant chemotherapy (n = 49); and predominantly localized disease (distribution: I = 91, II = 35, III = 58, IV = 5). Reverse phase protein array (RPPA) analysis was utilized to quantify 127 total or phosphorylated proteins. Interactions between protein expression and the receipt of neoadjuvant chemotherapy were assessed by analysis of variance (ANOVA). Cox regression was performed to determine the relationship between protein expression and recurrence-free survival (RFS).

Results: Twenty one of the 127 proteins (16%) were expressed at significantly different levels in patients receiving neoadjuvant chemotherapy. Specifically, patients receiving neoadjuvant chemotherapy had higher expression of multiple DNA repair proteins, including MSH2 (p&lt;0.001), 53BP1 (p = 0.01), and p-CHK1 (p = 0.02), as was Rb (p = 0.01), which regulates the expression of several proteins involved in DNA repair. Thymidylate synthase (TS), a target of the chemotherapeutic agent pemetrexed, also showed increased expression (p = 0.02). In addition, there was lower expression of phosphorylated proteins in the PI3K pathway, including p-70S6K (p = 0.008), p-mTOR (p = 0.02), and p-PDK (p = 0.02). Finally, we observed an expression of proteins indicative of an epithelial to mesenchymal transition (EMT), with lower expression of E-cadherin (p = 0.007) and Met (p = 0.03). Notably, there was also lower expression of COL6A, an excreted extracellular protein involved in cellular adhesion (p&lt;0.001), and a trend towards significance in increased expression of stathmin (p = 0.06), a microtubule destabilizer that has previously been implicated in EMT. Finally, we found that higher expression of multiple proteins involved in DNA repair were associated with a reduction in RFS after induction chemotherapy, including p-Rb (p = 0.015), CHK1 (p = 0.027), and p-CHK1 (p = 0.049).

Conclusions: The receipt of neoadjuvant chemotherapy was associated with higher expression of DNA repair proteins, suppression of the PI3K pathway, and an EMT shift. Increased expression of DNA repair proteins was also associated with reduced RFS. These findings suggest that higher expression of DNA repair proteins may contribute to treatment resistance, and support the combination of standard chemotherapy with targeted agents such as Chk inhibitors or immunotherapy (to address EMT-mediated immune escape).

Citation Format: Daniel R. Gomez, Lixia Diao, Jing Wang, Ignacio I. Wistuba, Cesar Moran, Neda Kalhor, Milind B. Suraokar, Stephen G. Swisher, Carmen Behrens, Youhong Fan, John V. Heymach, Lauren A. Byers. Neoadjuvant chemotherapy is associated with increased expression of DNA repair proteins and epithelial to mesenchymal transition (EMT) in patients with non-small cell lung cancer (NSCLC). [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 3623. doi:10.1158/1538-7445.AM2015-3623