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.

癌症的靶向治疗通常利用“癌基因成瘾”，即肿瘤细胞的生长和存活取决于特定蛋白质的活性的现象。然而，癌基因靶向治疗的疗效差异很大。例如，靶向表皮生长因子受体 (EGFR) 信号传导对某些非小细胞肺癌 (NSCLC) 有效，但对三阴性乳腺癌 (TNBC) 无效，尽管这些癌症显示出类似程度的 EGFR 活性增加。使用全基因组 CRISPR-Cas9 基因敲除筛选，我们发现 Elongator (ELP) 复合物通过促进抗凋亡蛋白 Mcl-1 的合成来介导 TNBC 细胞中对 EGFR 抑制剂厄洛替尼的不敏感性。消耗 ELP 蛋白以依赖于 EGFR 抑制的方式促进细胞凋亡。在一组遗传多样性的 TNBC 细胞中，Mcl-1 的药理学抑制与 EGFR 抑制协同作用。研究结果表明，TNBC 对 EGFR 信号传导的“成瘾”被 ELP 复合物掩盖，并且 TNBC 中对 EGFR 抑制剂的抗性可能会通过共同靶向 Mcl-1 来克服。