| Summary: | Resistance to chemotherapy is the major barrier in cancer therapy. Here, we aim to explore small molecules that reverse resistance to chemotherapy and examine the pathways employed to determine methods of preventing the cancer cell from evading death. We do so first by using both a hypothesis-driven approach to identify compounds that induce genes regulated by p53. We hypothesize that induction of these genes will alter the cell state so that in the face of DNA damage, p53 will signal apoptosis rather than arrest. We find that the signature does identify compounds known to sensitize tumors to radiation, but that they fail to do so in the conditions used in our study. In our second approach, we use an unbiased compound screen to identify small molecules that reduce cell viability in the context of low-dose daunorubicin. Here, we identify compound 3, which synergizes with both cisplatin and daunorubicin in chemo-resistant cells. Our evidence suggests that compound 3 elevates the levels of ER stress in the context of cisplatin and daunorubicin, resulting in apoptosis. Compounds identified in phenotypic screens are by definition hitting actionable targets. Enhancing ER stress is currently being investigated as a method to target cancer cells. Compound 3 may offer insight into ways to target this protein machinery. We find that both approaches can identify compounds that will enhance the apoptotic response of tumor cells faced with DNA damage.
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