P3.03-021 When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?: Topic: Mesothelioma Transitional

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Untreated, MPM has a median survival time of 6 months, and most patients die within 24 months of diagnosis. Therefore an urgent need exists to identify new therapies for treating MPM patients. The potential for therapeutically targeting receptor tyrosine kinase (RTK) signalling networks is emerging as a critical mechanism in ‘oncogene addicted’ cancer, with RTK inhibitors evolving as areas of considerable importance in cancer therapy. Furthermore, RTK hetero-dimerization has emerged as a key element in the development of resistance to cancer therapy. As such TKIs which target several RTKs may have superior efficacy compared with TKIs targeting individual RTKs. We and others have identified c-MET, RON, Axl and Tyro3 as RTKs frequently overexpressed and activated in MPM, making these attractive candidate therapeutic targets. A number of orally bioavailable small molecule inhibitors have been developed which can target these receptors. LCRF0004 specifically targets RON, whereas ASLAN002 (BMS-777607) or Merestinib (LY2801653) are orally bioavailable small molecule inhibitors which inhibit c-MET, RON, Axl and Tyro3 at nanomolar concentrations. These drugs may therefore have applicability in the treatment/management of MPM. A panel of MPM and normal pleural cell lines were screened for expression of Tyro3, c-MET, RON and Axl by RT-PCR, and subsequently examined in a cohort of patient samples comprising benign, epithelial, biphasic, and sarcomatoid histologies by qPCR. The effects of two small molecule inhibitors LCRF0004, ASLAN002 on MPM cellular health were assessed in vitro. The effects of LCRF0004 and ASLAN002 were subsequently examined in an in vivo SQ xenograft tumor model. Expression of various RON isoforms, c-MET, Tyro3 and Axl were observed in all cell lines. Significantly higher expression of all genes were found in the malignant tumor material versus benign pleura and this was validated in other datasets. Both LCRF0004 and ASLAN002 demonstrated significant anti-tumor efficacy in vitro. In xenograft models ASLAN002 was far superior to LCRF0004. Our results suggest that a multi-TKI, targeting the RON/MET/TAM signaling pathways, may be a more effective therapeutic strategy for the treatment of MPM as opposed to targeting RON alone.