Research ArticleCancer therapy

ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells

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Science Signaling  17 Nov 2020:
Vol. 13, Issue 658, eabb9820
DOI: 10.1126/scisignal.abb9820

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Unmasking drug sensitivity

Although the activity of the epidermal growth factor receptor (EGFR) pathway is increased in triple-negative breast cancers (TNBC), patients are generally insensitive to EGFR inhibitors. Cruz-Gordillo et al. found that this is because TNBC cells produced the prosurvival protein Mcl-1. A gene deletion screen revealed that insensitivity to the EGFR inhibitor erlotinib required MCL1 expression promoted by the ELP family of transcription-elongation regulators, particularly ELP4. The findings suggest that an ELP4–Mcl-1 mechanism masks erlotinib sensitivity in TNBC and that combining erlotinib with an Mcl-1 inhibitor might be effective in patients with TNBC.


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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