Novel markers of MCL1 inhibitor sensitivity in triple-negative breast cancer cells.
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ABSTRACT:
SUBMITTER: Duan L
PROVIDER: S-EPMC11208921 | biostudies-literature | 2024 May
REPOSITORIES: biostudies-literature
Publications
Novel markers of MCL1 inhibitor sensitivity in triple-negative breast cancer cells.
Duan Lei L Tadi Mehrdad Jafari MJ O'Hara Kelsey M KM Maki Carl G CG
The Journal of biological chemistry 20240516 6
Triple-negative breast cancer (TNBC) is an aggressive breast cancer sub-type with limited treatment options and poor prognosis. Currently, standard treatments for TNBC include surgery, chemotherapy, and anti-PDL1 therapy. These therapies have limited efficacy in advanced stages. Myeloid-cell leukemia 1 (MCL1) is an anti-apoptotic BCL2 family protein. High expression of MCL1 contributes to chemotherapy resistance and is associated with a worse prognosis in TNBC. MCL1 inhibitors are in clinical tr ...[more]
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Project description:Targeted therapeutics for cancer generally exploit "oncogene addiction," a phenomenon in which the growth and survival of tumor cells depend on the activity of a particular protein. However, the efficacy of oncogene-targeted therapies varies substantially. For instance, targeting epidermal growth factor receptor (EGFR) signaling is effective in some non-small cell lung cancer (NSCLC) but not in triple-negative breast cancer (TNBC), although these cancers show a similar degree of increase in EGFR activity. Using a genome-wide CRISPR-Cas9 genetic knockout screen, we found that the Elongator (ELP) complex mediates insensitivity to the EGFR inhibitor erlotinib in TNBC cells by promoting the synthesis of the antiapoptotic protein Mcl-1. Depleting ELP proteins promoted apoptotic cell death in an EGFR inhibition-dependent manner. Pharmacological inhibition of Mcl-1 synergized with EGFR inhibition in a panel of genetically diverse TNBC cells. The findings indicate that TNBC "addiction" to EGFR signaling is masked by the ELP complex and that resistance to EGFR inhibitors in TNBC might be overcome by cotargeting Mcl-1.
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