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The Kissil Laboratory

Research

Research in the Kissil lab focuses on mechanistic understandinghow mitogenic and developmental signaling pathways communicate in tumor cells and on the identification of therapeutic targets. The group employs multiple tools including molecular and cellular biology and development and use of animal models of human cancer.

Identifying vulnerabilities in Ras-driven tumorigenesis. The Ras genes are the most mutated oncogenes in cancer and as such present ideals target for therapeutic inhibition. This however has proven to be a formidable challenge and efforts have therefore focused on studying the signaling pathways regulated by Ras and identifying other effectors that are required for Ras-induced transformation, with the hope that these would present vulnerabilities to Ras-driven tumorigenesis. Over the past several years our groupfocused on identifying such targetsand understanding their function. These studies led to identification of the small G-protein Rac1 and the Notch1 receptor asrequired for Kras function in lung tumorigenesis. More recently, our group has developed and implemented novel High Throughput Screening (HTS) approaches to identify small molecules that are synthetic lethal to oncogenic K-ras. These approaches employ 3-dimensional formats that are thought to more closely reflect the conditions experienced by tumor cells in vivo. These efforts were successful in identifying synthetic lethal molecules that would not have been discovered employing traditional 2D culturing methods.We are currently using this approach in conjunction with a host of isogenic cell pairs to identify small molecules that are selectively lethal against cells carrying oncogenic mutations. We are incorporating. A host of chemoproteomic tools to identify the targets of these small molecules and determine how they function.

Our work on NF2 identified and validated a number of therapeutic targets including the p21-activated kinases (PAKs) ( Kissil et al., Mol. Cell. 2003; Yi et al., Cancer Res. 2008. Maksimoska et al., J. Am. Chem. Soc. 2008. Licciulli et al., J. Biol. Chem. 2013). In addition, we identified and determined the mechanism of action for Crizotinib, an FDA approved drug, as a potential drug treatment for NF2 associated schwannoma (Troutman et al., Oncotarget2016). This work led to the initiation of a phase-IIb clinical trial for NF2. More recently, we characterized the role of Hippo/Yap signaling in NF2 and identified previously unknown effectors in this pathway, the Angiomotins. The studieshave elucidated a mechanism through which Merlin regulates multiple signaling pathways from cell junctions (Yi et al., Cancer Cell. 2011, Yi et al., Science Sig. 2013). In addition, we characterized the role of Hippo/Yap signaling in NF2 and identified anobligate function for Yap in NF2, through transcriptional regulation of genes that promote survival of NF2-null Schwann cells mediated by a COX2/EGFR signaling axis. These studies also demonstrated in vivo that COX2 inhibitors could suppress tumor growth of NF2 schwannomas ( Guerrant et al., Cancer Res. 2016).

Since moving to the Scripps Research institute in late 2012, my group is engaged in efforts to identify small-molecule inhibitors of the Hippo/Yap pathway and develop novel imaging reporters to assess efficacy of therapeutics in vivo. These ongoing studies are conducted in close collaboration with multidisciplinary teams with world-class expertise in chemistry, proteomics, small molecule screening and antibody engineering. Our studies have resulted inmultiple peer-reviewed publications, demonstrating a record of successful and productive research, in an area of high relevance to human cancer.

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Understanding cell contact inhibition

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While normal cells possess mechanisms that suppress cell proliferation when conditions are inappropriate, tumor cells can circumvent these mechanisms. One such regulatory mechanism is triggered by a stimulus known as “cell-cell contact”, when cells reach acritical number and density. This “contact-inhibition” often becomes dysregulated during tumorigenesis. Over the past several years we have focused on how ”contact-inhibition” triggers anti-proliferative/growth control signals. A central player in the process is a protein called Merlin, which is the product of the NF2 (neurofibromatosis type 2) tumor suppressor gene. Recent studies have indicated the NF2 allele is functionally inactivated in a broad range of tumors and has been shown to function as a key regulator of multiple signal transduction pathways including those regulated by small G-proteins and the Hpo/Yap pathway. We recently identified the Angiomotins, members of the Motin protein family, as Merlin-interacting proteins that localize to tight and adherens junctions. And have determined that Merlin’s ability to regulate multiple downstream signaling pathways is mediated through the Angiomotins. We are working to determine how the Angiomotins function and whether the targeting these effectors might prove beneficial in the treatment of NF2.

 

Understanding the molecular basis of Neurofibromatosis Type 2 and identifying therapeutic targets.

NF2 is a dominantly inherited autosomal disease caused by loss of the NF2tumor suppressor gene. The NF2 gene codes forMerlin, a proteinthat predominantly localizes to the cell membrane. However, the mechanism/s through which Merlin exerted its function/s are incompletely understood. Moreover, there is an urgent need to develop therapeutic options for NF2 patients. Ourwork over the years identifiedMerlin as a regulator of a number of signaling pathways and potential therapeutic targets, including the p21-activated kinases (PAKs) and focal adhesion kinase (FAK). Through collaborations with organic/medicinal chemistsandstructural biologistsand weemployed structure-informed design approaches to identify and develop new classes of highly selective PAK inhibitors. Recent studies from ourgroup identified the FDA approved drug crizotinib, as a potential therapeutic for NF2-assoicatedschwannomaand determined the mechanism of action for this drug. We continue to study the molecular basis of NF2 and are currently focusing on another class of enzymes which play critical roles in NF2 tumor growth and assessing the consequences of therapeutic intervention in animal models of NF2.

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