Abstract 4802: PB1, a DDR2 inhibitor with antitumor activity in preclinical models of squamous cell carcinoma and KRAS-mutated adenocarcinoma of the lung
Authors: Garcia-Roman Silvia , Molina Miguel Angel , Borrell José Ignacio , Puig de la Bellacasa Raimon , Morales Daniela , Bertran Jordi , Gimenez Ana , Karachaliou Niki , Rosell Rafael 
Published: July 2016

Abstract
Introduction: Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase (RTK) activated by collagen I and identified as an oncogenic driver in squamous cell carcinoma of the lung (SCC) (1). DDR2 mutations have been reported in 4% of SCC patients and at lower frequencies in lung adenocarcinoma, gastric, breast and brain tumors (2). In addition, DDR2 is expressed during epithelial to mesenchymal transition (EMT) (3) and acts as an upstream activator of SHP2. SHP2 in turn is a key signaling effector which leads to activation of multiple signaling pathways (4). DDR2 has recently emerged as a potential therapeutic target in DDR2-mutated tumors and drugs such as dasatinib are being tested in this setting.
Results and discussion: PB1 is a small organic molecule with a simple synthesis pathway that showed strong inhibitory activity against wild type (wt) and mutated purified DDR2 protein. The compound was subsequently tested in a panel of tumor cell lines from different origins and histologies.
PB1 showed good antiproliferative activity: IC50&lt;1 μM in (i) SCC cell lines with DDR mutations such as H2286 or H520, (ii) SCC lung tumor cell lines wt for DDR2, and (iii) some lung adenocarcinoma cell lines with KRAS mutations such as A549. Remarkably, the two cell lines tested carrying the DDR2 activating mutation I638F were extremely sensitive to PB1, with IC50 in the nanomolar range. The compound also showed good activity against cells harboring the DDR2 L239R mutation. We also generated two dasatinib-resistant cells lines from the H2286 and H520 cell lines. Cells had IC50s for dasatinib over 25 uM but remained sensitive to PB1, with IC50s of 0.6 and 5.92, respectively. Finally, in non tumor cell lines, no toxicity was observed with PB1 at concentrations tested (up to 50 μM), indicating a good therapeutic index. Western blotting was used to study the effects of PB1 on DDR2, ERK and AKT activation in H2286 and A549 cells. The compound strongly inhibited FBS-induced phosphorylation of the three proteins.
Conclusion: PB1 shows significant antitumor activity in preclinical models of mutated and wt DDR2 in SCC of the lung and some KRAS mutated adenocarcinoma cell lines. PB1 is also active against tumor cells with secondary resistance to dasatinib.
References:
1) Hammerman et al. Cancer Discovery. 2011 June; 1: 78-89.
2) Terai et al. ACS Chem Biol. 2015 Sep; Epub ahead of print.
3) Walsh et al. Matrix Biol. 2011 May; 30(4): 243-247.
4) Iwai et al. Biochem. J. (2013) 454, 501-513.
Citation Format: Silvia Garcia-Roman, Miguel Angel Molina, José Ignacio Borrell, Raimon Puig de la Bellacasa, Daniela Morales, Jordi Bertran, Ana Gimenez, Niki Karachaliou, Rafael Rosell. PB1, a DDR2 inhibitor with antitumor activity in preclinical models of squamous cell carcinoma and KRAS-mutated adenocarcinoma of the lung. [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 4802.