Characterization of response and resistance mechanisms to targeted therapies in sarcoma:
Most human cancers with known actionable oncogenic drivers ultimately develop secondary resistance to targeted agents. Cancers dependent on constitutively active tyrosine kinase oncoproteins, for example, often respond dramatically to tyrosine kinase inhibitors but invariably contain subclones that manifest resistance, limiting the clinical benefit. The resistance mechanisms often involve either reactivation of the original oncoprotein, or activation of an alternate dysregulated oncogenic pathway which is often unknown.
With the overarching goal of designing therapeutic strategies able to suppress a broad range of polyclonal resistance mechanisms to targeted agents, we have developed representative sarcoma preclinical models consisting of isogenic drug-sensitive and drug-resistant cell lines, which we are analyzing with our functional genomics pipeline under different therapeutic selective pressures. We focus our efforts on resistance to KIT and multikinase inhibitors, MDM2 inhibitors, and PI3K inhibitors in specific types of sarcoma.