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

Abstract

One sentence summary:The Elongator Protein (ELP) Complex masks TNBC oncogene "addiction" to EGFR signaling, by promoting expression of the anti-apoptotic protein MCL1.Cruz-Gordillo et al. ABSTRACTTargeted therapies for the treatment of cancer are generally thought to exploit oncogene addiction, a phenomenon in which a single oncogene controls both the growth and survival of the tumor cell. Many well-validated examples of oncogene addiction exist; however, the utility of oncogene targeted therapies varies substantially by cancer context, even among cancers in which the targeted oncogene is similarly dysregulated. For instance, epidermal growth factor receptor (EGFR) signaling can be effectively targeted in EGFR-mutant non-small cell lung cancer (NSCLC), but not in triple-negative breast cancer (TNBC), where EGFR is activated to a similar degree. We find that EGFR controls a similar signaling/transcriptional network in TNBC and EGFR-mutant NSCLC cells, but only NSCLC cells respond to EGFR inhibition by activating cell death. To address this paradox and identify mechanisms that contribute to insensitivity to EGFR inhibition in TNBC, we performed a genome-wide CRISPR-Cas9 genetic knockout screen. Our screen identifies the Elongator (ELP) complex as a mediator of insensitivity to EGFR inhibition in TNBC. Depleting ELP proteins caused high levels of apoptotic cell death, in an EGFR inhibition-dependent manner. We find that the tRNA-modifying function of the ELP complex promotes drug insensitivity, by facilitating expression of the anti-apoptotic protein MCL1. Furthermore, pharmacological inhibition of MCL1 synergizes with EGFR inhibition across a panel of genetically diverse TNBC cells. Taken together, we find that TNBC "addiction" to EGFR signaling is masked by the ELP complex, and our study provides an actionable therapeutic strategy to overcome this resistance mechanism by co-targeting EGFR and MCL1.

Elp3‐mediated codon‐dependent translation promotes mTORC2 activation and regulates macrophage polarization

“…Alternatively, Elp3 may have stabilized Ric8b through mTORC2. Such hypothesis indeed explains how Elp3 stabilizes the anti‐apoptotic protein Mcl‐1 in triple negative breast cancers (Cruz‐Gordillo et al , 2020). The PI3K/mTOR pathway indeed stabilizes candidates such as Mcl‐1 (Wang et al , 1999).…”

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

“…Elongator (ELP) complexes can promote MCL-1 expression through tRNA modification, resulting in triplenegative breast cancer resistance to erlotinib. 307 Other mechanisms, such as gene hypomethylation, gene rearrangements, and silencing mutations in noncoding RNAs that regulate BCL-2, can also upregulate BCL-2. 303 However, some of these factors have not yet been demonstrated to be associated with TKI resistance.…”

Nanomaterial-assisted CRISPR gene-engineering – A hallmark for triple-negative breast cancer therapeutics advancement

“…2 ). The MCL-1 synthesis is upregulated by epidermal growth factor receptor ( EGFR ), and elongator complex ( ELP ) through the de novo signalling pathway [ 110 ]. However, in vivo aberration/upregulation of MCL-1 in TNBC carcinoma tissues positively links with extraordinary tumor proliferation and poor patient persistence.…”

“…It helps to investigate how overexpression or loss of function/complete gene silencing affects resistance/tolerance, immunosuppression, proliferation, invasion and metastasis in TNBC ( Table 3 ). For instance, TMEPAI [ 102 ], MCL-1 , EGFR [ 110 ], BAG3 [ 37 ], NSDHL [ 100 ], FOXC1 [ 4 ] , CXCR4 and CXCR7 [ 83 ] expression were seldom by CRISPR knockout gene-editing tool, while PTEN activation in TNBC via dead (d)-Cas9 merged with VP64-p65-Rta thereby repressing downstream AKT/mTOR/MAPK oncogenic signalling cascades [ 36 ]. Correspondingly, tRNA-based multiplex CRISPR/dCas9 aids in distinguishing diverse kinds of breast melanoma as HER2+, luminal A, luminal B and TNBC in OKMS1 cell line, where HER2+ proved as a possible lineage of luminal A, thereby shearing similar tumour stemness and treatment [ 229 ].…”

“…The plasmid-based CRISPR/Cas9 system, including pX333 [ 4 ], pX335 or pX330, pX459 [ 37 , 143 , 153 , 234 ], pcDNA-3.1 [ 13 , 89 , 274 ], pLKO-based plasmid [ 162 , 237 ], and dual vector bearing-plasmid system [ 83 , 110 ] is a modest and lucrative alternative approach for RNP, which signifies tractability in scheme owing to the affluence of DNA sequences integration into plasmids retaining unpretentious molecular cloning systems [ 94 ]. Nevertheless, the efficacy of gene engineering is frequently limited by gene expression proficiency and nuclear distribution, which is required to improve the critical gene therapy-dependent multiplexes.…”