RAF Dimer Inhibitor Treatment in Pediatric Acute Myeloid Leukemia
The NRAS and KRAS genes encode small proteins (N-Ras and K-Ras) that act as molecular switches. In normal cells, Ras proteins transiently bind to GTP wheh they are turned on - this stimulates growth through other proteins called effectors. Ras proteins are then turned off when GTP is converted to GDP. The NRAS and KRAS genes are mutated in many pediatric and adult cancers. These mutations result in the production of Ras proteins that can no longer efficiently convert GTP to GDP and behave like a switch that is on and can’t be turned off. This, in turn, causes abnormal activation of effector proteins and the uncontrolled growth that is a hallmark of cancer cells. The mitogen activated protein kinase pathway is comprised of three proteins (Raf, MEK, and ERK) that play a key role in driving the growth of cancer cells. When Ras is bound to GTP, it interacts with Raf, which then turns on MEK and ERK. Despite some recent progress in developing drugs that can directly inhibit Ras-GTP, this remains a very difficult problem in cancer drug discovery. By contrast, inhibitors Raf and MEK have been approved by the FDA to treat some types of tumors. However, the current drugs are largely ineffective in pediatric and adult cancers with NRAS or KRAS mutations for a variety of reasons.
Project Goal:
We will test a new type of Raf inhibitor called Belvarafenib in human acute myeloid leukemia (AML) cell lines and in mouse AMLs developed in our lab that harbor mutations in NRAS or KRAS (the mouse genes are called Nras and Kras, respectively). We will also ask if Belvarafenib might work better when it is combined with a MEK inibitior called Cobimetinib in AML. In studies performed to date, we have shown Belvarafenib and Cobimetinib work differently in AML cells and are more effective when given together. Our experimental goals are: (1) to learn more about how Belvarafenib and Cobimetinib work biochemically – both alone and together - to kill AML cells with NRAS or KRAS mutations; (2) to understand how AML cells become resistant to these drugs; and, (3) to do additional testing in pediatric AML cells.
AML accounts for ~20% of pediatric leukemia cases. In contrast to acute lymphoblastic leukemia (ALL), only 60% of children with AML are cured and treatment protocols has not markely improved over the past two decades. Current AML therapies are very toxic because they suppress the growth of normal bone marrow cells as well as having other side effects. Thus, new treatments that target N-Ras, K-Ras, and other mutant proteins essential for maligant growth are urgently needed. We hope that the results of our studies of Belvarafenib and Cobimetinib will lead to clinical trials of these drugs in AML and other pediatric cancers.
