Open AccessELP-dependent expression ofMCL1promotes resistance to EGFR inhibition in triple-negative breast cancer cells
Author(s) -
Peter CruzGordillo,
Megan E. Honeywell,
Nicholas W. Harper,
Thomas Leete,
Michael J. Lee
Publication year - 2020
Publication title -
science signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.659
H-Index - 154
eISSN - 1937-9145
pISSN - 1945-0877
DOI - 10.1126/scisignal.abb9820
Subject(s) - triple negative breast cancer , erlotinib , cancer research , mcl1 , breast cancer , chemistry , cancer , biology , medicine , downregulation and upregulation , epidermal growth factor receptor , gene , biochemistry
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.