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Early Molecular Responses to Treatment and Efficacy of Novel Therapeutic Combinations

Therapeutic inhibition of an oncoprotein silences the oncogene-dependent signaling, and activates upstream receptors and parallel compensatory pathways (silent in absence of oncogene inhibition) that limit the efficacy of the targeted therapy. Such adaptive resistance is well illustrated when rapamycin or rapalogs inhibit mTORC1, turning on a negative feedback loop via the insulin-like growth factor receptor, which finally activates Akt. In the same fashion, inhibition of PI3K/Akt in HER2-positive breast cancer cells leads to a compensatory activation of the ERK pathway, mediated by induction of HER3 expression leading to hyperphosphorylation of the HER receptors. Along with others, we have demonstrated that “synthetic lethality-like” effects can be achieved by disrupting theses adaptive pathways using combined targeted approaches.

We are testing the activity of PI3K inhibitors with MEK inhibitors, mTOR inhibitors, and agents that target upstream receptor tyrosine kinases.