The mechanisms of resistance and sensitivity to ischemia-like conditions in normal and malignant cells.
Simultaneous shortage of nutrients and oxygen, as happens under ischemia, is an extremely stressful condition for a mammalian cell. Organ ischemia frequently leads to organ failure. For example, ischemia is a common cause of acute kidney injury, which, in turn, is a major contributor to human mortality and morbidity worldwide. Our recent work utilized an unbiased genetic screen to identify multiple genes whose inhibition can improve survival of kidney cells in ischemia-like conditions. The findings offer insights into the strategies to prevent injury to the kidney and, possibly, other organs and tissues. We are interested in understanding the molecular mechanisms that determine the roles of the discovered genes in stress response, as well as in expanding the list of possible therapeutic targets beyond the candidates from our initial screen. Importantly, the lack of nutrients and oxygen is also an important factor in cancer progression. We are exploring how the various tumor adaptations to such a microenvironmental stress affect the future clinical trajectory of the disease.
The mechanisms of resistance and sensitivity to the inhibitors of MAP kinase cascade in human cancer.
Abnormal activation of the MAP kinase cascade is a common oncogenic event in human malignancies. One of the frequently mutated components of this pathway is a protein kinase encoded by BRAF gene. The recognition of hyperactive BRAF as the driver of many malignancies led to the emergence of therapeutic strategies to suppress its activity. This had a big impact on the management of metastatic melanoma, where BRAF mutations are common and inhibition of BRAF significantly improves survival. Unfortunately, some tumors are unresponsive to these drugs, while others develop resistance in the course of the treatment. We have identified several additional proteins that determine the response of cells to BRAF inhibitors. We are exploring these proteins as the predictors of clinical outcomes and as additional therapeutic targets to enhance the efficacy of anti-BRAF therapy.
Protein kinase Akt as a determinant of stress-resistance and -sensitivity in normal and malignant cells.
Protein kinase B, also known as Akt, is а key regulator of many processes in normal cells. In cancer, Akt gets hyper-activated. This phenomenon contributes to enhanced survival, growth, genetic instability and many other characteristic traits of oncogenically transformed cells. Overall, constitutive activation of Akt is one of the most common biochemical abnormalities in human malignancies. Often, it is a sign of a more aggressive or advanced disease. Importantly, in order to act as an oncogene, Akt depends on cooperation with certain other cellular factors. Furthermore, constitutive activation of Akt is a very stressful event for a normal cell and requires additional adaptations to be tolerated. We are exploring specific dependencies and vulnerabilities associated with oncogenic activation of Akt. Our long-term goal is to use this information to selectively suppress or eliminate cancer cells while sparing normal tissues.
MicroRNAs and their regulation in normal and cancer cells.
MicroRNAs control translation and stability of mRNA and are important determinants of the repertoire and abundance of proteins in mammalian cells, both in health and in disease. We studied and reported the regulation of miRNA expression by NF-kB and FOXO1 transcription factors. More recently, we reported the evidence that a previously unrecognized miRNA can be generated from the transcript of DROSHA gene, and this miRNA may attenuate DROSHA production. Our findings suggest the existence of a negative feedback loop whereby DROSHA keeps its activity in check by producing out of its own mRNA an inhibitor of its translation. Considering that DROSHA is a key enzyme in the classical miRNA biogenesis pathway, it is likely that the proposed mechanism has a global effect on the process of RNA interference in human cells.