Missense mutations in protein kinases have been found to induce constitutive activation and drive tumorigenesis in various types of cancer, thus making them an ideal therapeutic target. The FDA has approved several drugs that target specific kinases in a subset of cancers, effectively suppressing their activity and leading to tumor regression. However, tumors almost universally develop resistance. Due to this, it is important to elucidate the landscape of resistance mechanisms to adequately treat and control oncogenic activity in cancer where kinase targeted therapy is being utilized. We have deployed comprehensive, saturation mutagenesis of a series of Ser/Thr kinases to elucidate general, and broadly applicable, mechanisms of kinase activation through missense mutations. These studies revealed mutations in poorly characterized, yet highly conserved, structural regions of Ser/Thr kinases that induce constitutive activation of the kinase and additionally render them resistant to kinase-directed small molecule inhibitors, many of which are currently in clinical trials. This region is functionally conserved in other kinases, suggesting a broad mechanism of kinase activation and drug resistance. By utilizing site-specific mutagenesis, we aim to test this hypothesis in other kinases to determine its broad applicability. Kinase inhibitors have become crucial to the treatment of cancer and understanding resistance mechanisms will allow better therapeutic approaches that may ultimately increase the efficiency of treatment.
PROJECT: Uncovering mechanisms of resistance in a subset of kinases
Working at the Broad this summer has opened my eyes to the power of collaboration in scientific research. Being immersed in this rich environment allowed me to gain important skills that will help me advance in my career as a young scientist.