Abstract B101: TrkB (NTRK2) as a potential therapeutic target in NSCLC in combination with EGFR TKIs
Authors: Hofstad Mia E. , Gomez Daniel R. , Nilsson Monique B. , Byers Lauren A. , Diao Lixia , Wang Jing , Li Lerong , Tong Pan , Heymach John V. 
Published: August 2018

Squamous cell carcinomas (SCC) account for approximately 25-30% of all non-small cell lung cancer (NSCLC) cases. To date, a limited number of therapeutic targets have been identified for SCC NSCLC; thus there is a critical need to identify novel, effective therapeutic regimens for this patient population. We utilized reverse phase proteomic arrays (RPPA) from two cohorts of early-stage NSCLC patients to investigate potential therapeutic targets overexpressed in SCC NSCLC. We identified tropomyosin receptor kinase B (TrkB) as being overexpressed in SCC NSCLC compared to non-SCC NSCLC. Using a panel of NSCLC cell lines, we determined that phosphorylated TrkB levels were significantly elevated in SCC NSCLC cell lines compared to adenocarcinoma NSCLC cell lines. Treatment with the TrkB inhibitor, AZD7451, significantly reduced the constitutive activation of TrkB and decreased phosphorylation of downstream signaling components, including Erk and AKT in HCC95 cells (SCC). The addition of the TrkB ligand, BDNF, resulted in a modest increase in TrkB phosphorylation in H1703 cells (SCC), which was blocked with the addition of AZD7451. We next investigated the role of TrkB in facilitating tumor cell invasiveness. Treatment of A549 cells (adenocarcinoma NSCLC) with exogenous BDNF significantly enhanced tumor cell migration, which was blocked with the addition of AZD7451. However, the effects of TrkB activation on cell migration were cell line specific as BDNF did not enhance tumor cell migration in H460 or H23 cells. Given prior publications suggesting potential crosstalk between epidermal growth factor receptor (EGFR) and TrkB, we sought to determine whether crosstalk between EGFR and TrkB occurs in squamous cell carcinoma cells. Although evidence of crosstalk was heterogeneous among cell lines, EGF stimulation increased activation of TrkB in Cal27 (head and neck SCC), and this effect was blocked by the EGFR tyrosine kinase inhibitor (TKI), erlotinib. Moreover, in vitro cell viability assays demonstrated a synergistic effect of erlotinib in combination with AZD7451 in both adenocarcinoma and SCC cell lines. Taken together, these findings indicate that TrkB is a potential therapeutic target in a subset of SCC NSCLC patients and that the antitumor activity of TrkB-targeting agents may be potentiated by EGFR inhibition. In addition, our findings suggest that activation of the TrkB pathway may drive an invasive phenotype in a subset of NSCLCs.

Citation Format: Mia E. Hofstad, Daniel R. Gomez, Monique B. Nilsson, Lauren A. Byers, Lixia Diao, Jing Wang, Lerong Li, Pan Tong, John V. Heymach. TrkB (NTRK2) as a potential therapeutic target in NSCLC in combination with EGFR TKIs [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B101.