Abstract 4802: PB1, a DDR2 inhibitor with antitumor activity in preclinical models of squamous cell carcinoma and KRAS-mutated adenocarcinoma of the lung

Abstract

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<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.