Characterizing the non-catalytic functions of Akt in cancer
The catalytic functions of Akt have been and continue to be widely studied. Our research has uncovered novel functions of Akt that do not require kinase activity, and which can promote survival and proliferation. Furthermore, kinase-inactivating mutations have been found in human cancers, particularly in melanoma. We have validated the kinase-inactivating nature of these mutations in a subset of mutants, and are now beginning to examine their biological properties.
We plan to assess their transforming ability either alone, or in combination with other commonly occurring lesions such as N-RAS or B-RAF mutations. We also plan to characterize the signaling properties of these mutants using mass spectrometry and transcriptomic approaches.
Using Metabolo-Oncogenic Counter-Addiction (MOCA) as a platform for target identification.
The unusual dependence of cancer cells on the activity of a single gene product (i.e. oncogene addiction) stems from the inability of the cancer cell to “buffer” acute changes in survival signals such as those caused by inhibition of the addicting activity. This apparent lack of plasticity in cancer cells is the basis for targeted therapies, such as those used to treat mutant EGFR non-small cell lung carcinoma (NSCLC), and mutant-braf malignant melanoma. Furthermore, it has been shown that like inhibition, overstimulation of the driver oncogene (e.g. EGFR), can also result in cell death, suggesting that in the oncogene addicted state, cell survival can be compromised by either too little or too much oncogene activity (Fig).
Interestingly, metabolic dependencies often accompany oncogene addiction, and these metabolic addictions also seem to be dependent on the activation of specific signaling pathways. For example, oncogenic activation of c-Myc has been linked to an acquired dependence on glutamine consumption, and Akt activation has been shown to render cells dependent on glucose for cell survival. Although significant progress has been made in understanding how oncogenes regulate metabolic pathways, much less is known about the impact of metabolic states on signal transduction.
My preliminary data show that in EGFR-addicted glioblastoma (GBM) cells, EGFR becomes “superactivated” by glucose starvation. Notably, glucose-deprivation-induced cell death (GDICD) in these cells can be blocked by EGFR inhibition, suggesting that it is the superactivation of EGFR that initiates the cell death program. This phenotype does not seem to be restricted to EGFR. For example, we have observed that glucose deprivation or treatment with Braf inhibitors, while individually cytotoxic to a mutant Braf melanoma cell line, cannot induce any significant cell death when given as concurrent treatment. Our group has named this phenomenon Metabolo-Oncogenic Counter-Addiction (MOCA).
It is likely that these two types of cytotoxicity (i.e. inhibitor-initiated and glucose-starvation-initiated) are regulated by distinct signal transduction pathways. Therefore, the molecular characterization of these signals can potentially lead to the identification of novel therapeutic targets responsible for oncogene-dependent metabolic addiction.
Our lab is studying and characterizing the interplay between metabolism and oncogene signal transduction, and the potential therapeutic implications of these interactions. Specifically, we will catalogue the transcriptional and phospho-proteomic changes caused by inhibition of EGFR and of Braf both in the presence or absence of glucose.
We also plan to investigate the feasibility of targeting “death suppressing signals,” that is, phosphopeptides or transcriptional changes that are selectively enriched by kinase inhibitor under hypoglycaemic conditions (i.e. during MOCA) but not under normoglycemic conditions (i.e. during a normal oncogene addiction response)