Interruption of cholesterol metabolism and replication stress response in cancer therapy

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Project Summary: Lung cancer is the most common malignancy worldwide, both in incidence and mortality. Unfortunately, this disease is often driven by activating oncogenes that are either not amenable to direct therapeutic intervention or when targeted therapies are available treatment resistance invariably develops, thus highlighting the urgent need for the development of novel treatment strategies. Metabolic reprogramming is a hallmark of cancer and is a pharmaceutical target for cancer therapy. SQLE, a key enzyme required for cholesterol synthesis, is frequently overexpressed in lung cancer and is associated with poor prognosis. Excitingly, our recent genome-wide loss of function screen discovered that SQLE reduction caused enhanced sensitivity to an inhibitor targeting CHK1, a key DNA damage response (DDR)/replication stress (RS) response protein that is required for cell survival and proliferation under RS. Our preliminary data suggest that SQLE inhibition by shRNA knockdown causes RS and activates ATR/CHK1 signaling. Thus, the goal of this application is to determine whether high SQLE-expressing lung cancer can be specifically targeted by the combined inhibition of SQLE and CHK1 or its upstream factor ATR. Because the inhibition of proteins required for cholesterol biosynthesis leads to decreased dNTP and increased reactive oxygen species (ROS) (i.e., two common mechanisms for RS ), we hypothesize that SQLE inhibition leads to increased RS by deregulation of dNTP and/or ROS, triggering the ATR/CHK1 axis for survival. Thus, co-administration of an SQLE inhibitor and an ATR or CHK1 inhibitor could synergistically suppress tumor growth of lung cancer. Specific Aim 1 will delineate whether SQLE inhibition-induced RS is associated with perturbation of the dNTP pool and increased ROS, using liquid chromatography-tandem mass spectrometry, DNA fiber assays and biochemical/cell biological approaches. Specific Aim 2 will assess the antitumor effects of the combined inhibition of SQLE and RS response proteins using in vitro assays and cell line-based and patient-derived xenograft (PDX) mouse models of lung cancer. If successful, our studies will have a significant impact on improving the survival of lung cancer patients by identifying novel therapeutic approaches.