Mutationally activated Ras genes (Hras, Kras, and Nras) comprise the most frequently mutated gene family in cancer. KRAS is the isoform mutated exclusively in pancreatic ductal adenocarcinoma (PDAC) and it is found in nearly all PDACs, making pancreatic cancer arguably the most Ras-addicted cancer. Activating mutations of Kras are the main genetic drivers of PDAC and are essential for its initiation and maintenance. The National Cancer Institute identified targeting KRAS as one of four major priorities for pancreatic cancer research. Unfortunately, currently there are no approved drugs that target mutated KRAS proteins directly. There are drugs that target KRAS indirectly by blocking its interacting proteins (downstream effectors, members of the signaling pathways) , but they have been ineffective against pancreatic cancer in clinical studies. This is mostly due to the fact that cancer cells have ensured compensatory mechanisms that overcome the effectiveness of inhibitors when used as a monotherapy and allow cells to acquire resistance to the therapy. Combination approaches are therefore necessary to achieve a prolonged antitumor response that is less vulnerable to mechanisms of acquired resistance.
It was recently shown that the suppression of KRAS, as well as its downstream effectors (RAF/MEK/ERK) leads to the deregulation of cellular processes that support increased metabolic needs of cancer cells. Specifically, it was observed that blocking MEK/ERK leads to an increase of autophagic flux, suggesting that this inhibition may be enhancing PDAC dependence on autophagy. Autophagy, a lysosome-mediated process, allows cells to degrade organelles and macromolecules and recycle the intermediates to sustain cell metabolism, critical for tumor growth. Several mechanisms have been proposed for how autophagy may support tumor growth in PDAC, including not only providing metabolic fuel sources but also allowing cancer cells to deal with a variety of stressors. It has also been shown that autophagy inhibition decreased proliferation and increased DNA damage and apoptosis in PDAC. The discovery of this dependence made recently by two independent research teams led to the development of two-drug regimen that blocks MEK/ERK and autophagy pathways and produces consistent synergistic responses in cell lines, in several transplantation models, and most importantly in a set of human PDA patients.
With my work I intend to test the efficacy of this drug combination in several Genetically Engineered Mouse Models (GEMMs) such as KPC or KPffC used by our lab. I will then utilize these models to further explore complex in vivo mechanisms of response to combination therapy, and well as potential mechanism by which cancer cells adapt/acquire resistance to the treatment. Use of GEMMs will specifically allow to look at the tumor microenvironment and responses of different cell populations.
It was recently shown that the suppression of KRAS, as well as its downstream effectors (RAF/MEK/ERK) leads to the deregulation of cellular processes that support increased metabolic needs of cancer cells. Specifically, it was observed that blocking MEK/ERK leads to an increase of autophagic flux, suggesting that this inhibition may be enhancing PDAC dependence on autophagy. Autophagy, a lysosome-mediated process, allows cells to degrade organelles and macromolecules and recycle the intermediates to sustain cell metabolism, critical for tumor growth. Several mechanisms have been proposed for how autophagy may support tumor growth in PDAC, including not only providing metabolic fuel sources but also allowing cancer cells to deal with a variety of stressors. It has also been shown that autophagy inhibition decreased proliferation and increased DNA damage and apoptosis in PDAC. The discovery of this dependence made recently by two independent research teams led to the development of two-drug regimen that blocks MEK/ERK and autophagy pathways and produces consistent synergistic responses in cell lines, in several transplantation models, and most importantly in a set of human PDA patients.
With my work I intend to test the efficacy of this drug combination in several Genetically Engineered Mouse Models (GEMMs) such as KPC or KPffC used by our lab. I will then utilize these models to further explore complex in vivo mechanisms of response to combination therapy, and well as potential mechanism by which cancer cells adapt/acquire resistance to the treatment. Use of GEMMs will specifically allow to look at the tumor microenvironment and responses of different cell populations.
