The role of LZTR1 in cancer development and progression

The RAS pathway is one of the most commonly activated signaling nodes in human disease. Despite more than three decades of intensive effort, the task of developing effective therapeutic strategies for RAS-driven disease remains daunting. About one-third of human cancers have somatic mutations in one of the RAS genes (HRAS, NRAS, KRAS4A, and KRAS4B). KRAS mutations are present in 20% to 25% of patient with lung cancer. Lung cancer is the leading cause of cancer death worldwide, causing up to 18% of all cancer deaths, with lung adenocarcinoma (LUAD) being the most common lung cancer. Oncogenic mutations of KRAS are found in up to one-third of LUAD. Interestingly, oncogenic mutations of KRAS significantly co-occur with LZTR1 shallow deletions in LUAD (q-value 0.047, TCGA data), suggesting LZTR1 los of function might contribute to KRAS-driven tumorigenesis. Germline mutations LZTR1, a gene encoding an E3 ubiquitin ligase adaptor, have been associated to the familial Schwannomatosis. Schwannomatosis is benign but causes morbidity in the form of pain, neurologic disability or organ compression. The only treatment options are surgery and only a few animal models of the disease exist. Germline LZTR1 mutations account for up to 40% of the cases of familial schwannomatosis, and are always associated to somatic loss of the 22q chromosomal region containing LZTR1, suggesting that LZTR1 LOF could trigger Schwannoma development. In this project, I will determine the role of LZTR1 in cancer development and progression in both wild type and mutant KRAS cancers. Furthermore, I aim to assess the molecular mechanisms of mutant KRAS ubiquitination in cancer development and progression.