Multilayer investigation of resistance mechanisms to WEE1 inhibition in Small Cell Lung Cancer
Abstracts
Initial Award Abstract |
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Mammalian cells have adapted precise mechanisms that minimize possibilities for error during cell division. The disruption of these mechanisms is often associated with the development of human diseases such as cancer. My proposal focuses on the concept that while DNA mutations can promote cancer, the accumulation of too many mutations in a cancer cell can be exploited to kill this cell. SCLC is an aggressive lung cancer, mainly caused by heavy smoking, and is driven by inactivating mutations in two key cell cycle genes, RB and p53. These mutations mostly affect the early steps of the cell cycle but are not readily druggable. Interestingly, however, drugs targeting late stages of the cell cycle progression have been recently developed. It has been proposed that disrupting these late cell cycle steps in cancer cells in which the early steps are already disrupted, may lead to catastrophic cell division and cell death. The cancer genome accumulates many mutations and if the cancer cell is unable to repair them before dividing, this may lead to cell death. Indeed, these drugs, including inhibitors of the WEE1 protein, involved in a late stage of cell division (mitosis), have shown promising results in SCLC patients; however, evidence of resistance to treatment has also already emerged from these studies.
My project aims to elucidate the mechanisms that control how cells respond to WEE1 inhibition, why they sometimes become resistant to this inhibition, and how to resensitize them with combinational treatments. In brief, I have performed unbiased genome-wide screens in SCLC cells to identify genes whose loss of function may regulate how SCLC cells respond to WEE1 inhibition. From these screens, I have already uncovered candidate genes important for WEE1 inhibition resistance and sensitivity. I will use unique tools developed in the Sage lab, including mouse models, to identify additional candidates and validate top candidate genes involved in WEE1 resistance. I will also examine the role of these candidates at the single cell level, which allows to determine how key signaling pathways respond to specific genetic mutations in single cells within heterogeneous populations. I hope that these experiments will identify novel therapeutic strategies in SCLC and other cancer types. |
