TP-0903 (AXL Kinase Inhibitor)
TP-0903 is a potent anti-cancer agent targeting the AXL receptor tyrosine kinase that has demonstrated profound activity in several cell-based and animal models of cancer. Therefore, TP-0903 has multiple paths of development that are being explored by Tolero.
AXL and other TAM family members are known to be involved in maintaining a mesenchymal phenotype in cancer cells. Mesenchymal cells have increased invasion and migratory properties, enhanced cell survival in stressed environments, and increased resistance to targeted therapies. In fact, AXL overexpression is a reoccurring theme observed in multiple tumor types that have acquired resistance to various agents.
Treatment of cancer cells with TP-0903 reverses the mesenchymal phenotype in multiple models and sensitizes cancer cells to treatment with other targeted agents. AXL-induced resistance to erlotinib in EGFR mutant lung cancer and cetuximab resistance in head and neck cancer exemplify this phenomenon. TP-0903 restores sensitivity to erlotinib in cell-based and preclinical animal models of cancer by reversing the mesenchymal phenotype driving resistance. Additionally, Tolero is exploring parallel clinical development paths in ibrutinib-progressing patients with B-cell malignancies and FLT3 inhibitor resistance in acute leukemias.