Targetting molecular addictions in cancer

Cancer cells depend on a finite number of critical signals for their survival. Oncogene addiction, that is, the acquired dependence of a cancer cell on the activity of a single oncogenic gene product, has been the basis for the targeted therapy paradigm, and operationally defines such signals. Additionally, cancer cells have altered metabolic requirements that create addictions to specific nutrients such as glucose.
The identification of suitable therapeutic targets in cancer (e.i. oncogene addictions) has extensively relied on genetic profiling of tumors and the cataloguing of the most common activating lesions targeting suspected (or bona fide) oncogenes.
Although the identification of such mutations has guided the successful development of a number of now FDA-approved agents, not all recurring mutations have met with this kind of success. De novo resistance to inhibitors that target recurrently mutated oncoproteins has been observed, which raises the question of whether the cancer cell may not have developed an addiction to the target, or whether the pharmacological approach has been inadequate.
My work has focused on three closely related fronts. First, I have conducted functional studies to characterize the molecular basis of de novo resistance to EGFR inhibitors. These studies have provided evidence that inactivation of the tumor suppressor PTEN can impair EGFR signal termination creating a “right-shift” in both the biochemical and biological response to EGFR inhibitors. I have also found that different activating EGFR mutations can differentially alter the conformation of the mutant receptor in a way that defines their sensitivity to different types of ATP-competitive kinase inhibitors. Second, using pharmacological probing to identify Akt addictions, I have found and began to characterize a novel kinase-independent pro-survival function of Akt in both non-small-cell lung carcinoma and breast cancer. Third, although glucose addiction, a prediction of the Warburg effect, has been well documented in cancer cells, how or whether it is associated to specific oncogene addictions has not been extensively studied. My work on this front is based on the observation that glucose deprivation of oncogene-addicted cells promotes cell death through oncogene overdose, that is, the super-activation of the driver oncogene, rather than through a simple depletion of energy.