Lysosomes at the crossroads between CDK4 and mTOR pathway

Cancer is the name given to a group of related diseases characterized by uncontrolled cell growth and proliferation. In this project, we focused on the cell cycle regulator Cyclin-dependent kinase 4 (CDK4), which contributes to cell proliferation. Since this protein is commonly deregulated in cancer, CDK4 inhibitors have become a useful therapeutic tool for cancer treatment. The function of this protein is not limited to the control of the cell cycle; CDK4 also participates in the control of metabolism, always favoring anabolism and repressing catabolism. However, the exact mechanism by which CDK4 controls cell metabolism is not yet elucidated. It has been recently shown that CDK4 cross-talks with the master regulator of cell growth and metabolism, mammalian target of rapamycin (mTOR). This protein has also been effectively targeted in cancer treatments, since it is commonly hyperactive in cancer cells to maintain protein synthesis, cell growth and other anabolic processes. mTOR functions as two complexes: mTOR complex I (mTORC1) and mTOR complex II (mTORC2). Lysosomes, the main degradative organelles of the cell, are crucial for mTORC1 activation; mTORC1 is recruited to the surface of these organelles in response to extrinsic amino acids, or amino acids originated by the lysosomal degradation of macromolecules. Here, we show that, on one hand, CDK4 phosphorylates FLCN, a regulator of mTORC1 translocation to the lysosomal surface, thus facilitating mTORC1 activation. On the other hand, we demonstrate that CDK4 promotes lysosomal degradation, which also results in mTORC1 activation. Finally, and most importantly for cancer therapy, we take advantage of this novel function of CDK4 to propose a new therapeutic strategy to treat triple-negative breast cancer (TNBC). We combined a CDK4 inhibitor, which impairs lysosomal function, with an inducer of autophagy (a degradative process in the cell in which lysosomal function is required) to trigger cancer cell death. Overall, this project describes a novel role for CDK4 in the control of lysosomal biology and the mTOR pathway in cancer cells, and proposes a promising therapeutic strategy for cancer treatment