Myeloid cell leukemia 1 (Mcl-1) inhibitor to enhance DNA replication stress sensitivity for cancer therapy.
Chemoresistance occurs when cancer cells develop resistance to chemotherapy drugs, and appearance of chemoresistance greatly worsens the prognosis of cancer patients. Some chemotherapy drugs function by causing DNA breakages, including double strand breaks (DSBs). DSBs are repaired using either non-homologous end joining or homologous recombination (HR). These repair mechanisms allow cancer cells to resist DNA damage caused by chemotherapy drugs and develop resistance to the drugs. There is a need for improved therapies for cancer that can prevent or reverse chemoresistance.
Emory researchers have screened and identified small molecule inhibitors of myeloid cell leukemia 1 (Mcl-1). Mcl-1 is an anti-apoptotic protein associated with DSB repair. Mcl-1 is overexpressed in cancer cells and correlated with resistance to chemotherapy and radiation. These small molecules inhibit HR activity and strongly synergize with DNA replication stress agents against lung cancer in vitro and in vivo. The identified compounds may have applications as a combination therapy to inhibit Mcl-1-stimulated HR DNA repair in a variety of cancers.
Publication: Chen, G. et al. (2018). J Clin Invest, 128(1), 500-516.
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