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

Abstract

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.

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

“…MUC1-C has additionally been determined to activate the transcription of BCL2A1 in an NF-κB-dependent manner in TNBC cells [ 220 ]. Recently, upregulation of MCL1 by elongator (ELP) complex has been reported to mediate resistance to the EGFRi erlotinib [ 260 ]. Depletion of ELP proteins, such as ELP3, ELP4, ELP5, and ELP6, sensitized TNBC cells to erlotinib, while ELP4 -KD reduced expression of MCL1 in the TNBC cells in the presence of erlotinib.…”

“…As mentioned earlier (see Section 3.4.2 . Overexpression of Anti-apoptotic Proteins), MCL1 has been reported to confer EGFRi resistance in an ELP complex-dependent manner [ 260 ]. In addition, co-treatment of the MCL1 inhibitor S63845 synergistically induced erlotinib sensitivity in TNBC cells.…”

Cooperative regulation of coupled oncoprotein translation and stability in triple-negative breast cancer by EGFR and CDK12

“…Second, a number of reports have described cooperativity between EGFR blockade and inhibition of receptor tyrosine kinase (RTK)-PI3K-mTOR signaling in TNBC (El Guerrab et al, 2020; You et al, 2018; Simiczyjew et al, 2018; Verma et al, 2017; Tao et al, 2014; Sohn et al, 2014). A recent report also demonstrated that the effects of EGFR inhibition can be potentiated through blockade of Elongator complex-mediated MCL-1 translation (Cruz-Gordillo et al, 2020). While these studies revealed sensitizing effects that appear to be significantly less profound, and more heterogeneous, than those reported here, it remains to be determined if these processes regulate, or are regulated by, CDK12.…”

“…While attempting to identify oncogenic drivers in TNBC, immunohistochemical and large-scale genomic studies have suggested that EGFR signaling may be frequently activated and associated with poor prognosis (Park et al, 2014; Cancer Genome Atlas Network, 2012; Hoadley et al, 2007; Nielsen et al, 2004). These findings have long positioned EGFR as an intriguing target in TNBC; however, efforts to target EGFR in unselected TNBC patients have yielded low response rates (Baselga et al, 2005; Fountzilas et al, 2005; Carey et al, 2012; Baselga et al, 2013; Corkery et al, 2009; Ali and Wendt, 2017, Cruz-Gordillo et al, 2020). This is indicative of possible intrinsic resistance and its underlying mechanisms as a major impediment to more widespread use of EGFR inhibitors in TNBC.…”

Patient-Specific Network for Personalized Breast Cancer Therapy with Multi-Omics Data

“…MCL1 belongs to the BCL2 family and is a negative modulator of apoptosis. Amplifications of MCL1 are observed in several human cancers such as breast, lung, and ovarian cancers [ 42 ]. A recent study suggested that MCL1 inhibitors could have a role in estrogen receptor-positive BC blocking cell survival [ 43 ].…”