The laboratory is studying small molecules that selectively inhibit the components of RAS-RAF-MEK-ERK and PI3K-AKT-mTOR pathways. These compounds are being used as reagents to define the role of these pathways in tumors with the goal of developing strategies for using these agents in patients.
One major focus of our lab is the study and development of selective inhibitors of the ERK pathway to treat the tumors driven by ERK hyperactivation. Previously we found that activation of ERK output is dependent upon the mechanisms by which oncogenic mutants evade ERK-dependent feedback regulation. The loss of feedback regulation not only drives constitutive activation of the ERK pathway, but also sensitizes the tumors to specific inhibitors of pathway components. As we have reported, the BRAF and RAS mutant tumors are more sensitive to ERK pathway inhibition than the RAF/RAS wild type tumors. We are now investigating the biochemical actions and anti-tumor activities of the different inhibitors (mutant RAS selective inhibitors, RAF monomer selective inhibitors, RAF dimer inhibitors, allosteric MEK inhibitors, ATP-competitive MEK inhibitors, and ERK inhibitors) in tumors expressing different RAS, RAF, or NF1 mutants.
We have shown that tumors with HER2 amplification or PI3K mutation are selectively dependent for growth on the PI3K pathway and are sensitive to specific inhibitors of PI3K or AKT. Inhibition of PI3K signaling in tumors has metabolic, pro-apoptotic, and anti-proliferative effects, but relief of potent feedback inhibition of upstream receptors increases their activation and expression, attenuating the antitumor benefit of the drugs. We have shown that inhibitors of PI3K, AKT, and mTOR all relieve feedback, but the details of their effects differ, which suggests why these drugs vary in their in efficacy and toxicity. This work has enhanced our understanding of the oncogenic signaling network, with implications for developing more effective therapeutic strategies.
The evaluation of Hsp90 as a therapeutic target in cancer patients is another major focus of our lab. Hsp90 is a chaperone required for maintaining the proper conformation of several important signaling proteins, including transmembrane tyrosine kinases and steroid receptors. The laboratory is studying the role of Hsp90 family members in maintaining the transformed phenotype of cancer cells. Our recent work has shown that Hsp90 is critical for oncogenic RAF kinase-driven ERK activation. The combination of Hsp90 inhibitors with RAF or MEK inhibitors may achieve a better pathway inhibition in RAS and/or BRAF mutant tumors. This work will contribute significantly toward better patient treatments.