Garcia Nina Marie G, Becerra Jessica N, McKinney Brock J, DiMarco Ashley V, Wu Feinan, Fitzgibbon Matthew, Alvarez James V
Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Center.
Department of Pharmacology and Cancer Biology, Duke University School of Medicine.
bioRxiv. 2024 Nov 20:2023.07.02.547443. doi: 10.1101/2023.07.02.547443.
APOBEC mutagenesis is one of the most common endogenous sources of mutations in human cancer and is a major source of genetic intratumor heterogeneity. High levels of APOBEC mutagenesis are associated with poor prognosis and aggressive disease across diverse cancers, but the mechanistic and functional impacts of APOBEC mutagenesis on tumor evolution and therapy resistance remain relatively unexplored. To address this, we investigated the contribution of APOBEC mutagenesis to acquired therapy resistance in a model of EGFR-mutant non-small cell lung cancer. We find that inhibition of EGFR in lung cancer cells leads to a rapid and pronounced induction of APOBEC3 expression and activity. Functionally, APOBEC expression promotes the survival of drug-tolerant persister cells (DTPs) following EGFR inhibition. Constitutive expression of APOBEC3B alters the evolutionary trajectory of acquired resistance to the EGFR inhibitor gefitinib, making it more likely that resistance arises through acquisition of the T790M gatekeeper mutation and squamous transdifferentiation during the DTP state. APOBEC3B expression is associated with increased expression of the squamous cell transcription factor ΔNp63 and squamous cell transdifferentiation in gefitinib-resistant cells. Knockout of p63 in gefitinib-resistant cells reduces the expression of the ΔNp63 target genes IL1α/β and sensitizes these cells to the third-generation EGFR inhibitor osimertinib. These results suggest that APOBEC activity promotes acquired resistance by facilitating evolution and transdifferentiation in DTPs, and suggest that approaches to target ΔNp63 in gefitinib-resistant lung cancers may have therapeutic benefit.
载脂蛋白B编辑酶催化的突变是人类癌症中最常见的内源性突变来源之一，也是肿瘤内基因异质性的主要来源。高水平的载脂蛋白B编辑酶催化的突变与多种癌症的预后不良和侵袭性疾病相关，但载脂蛋白B编辑酶催化的突变对肿瘤进化和治疗耐药性的机制及功能影响仍相对未被探索。为了解决这个问题，我们在表皮生长因子受体（EGFR）突变的非小细胞肺癌模型中研究了载脂蛋白B编辑酶催化的突变对获得性治疗耐药性的作用。我们发现，抑制肺癌细胞中的EGFR会导致载脂蛋白B3表达和活性迅速且显著的诱导。在功能上，载脂蛋白B表达促进了EGFR抑制后耐药性持久细胞（DTPs）的存活。载脂蛋白B3B的组成型表达改变了对EGFR抑制剂吉非替尼获得性耐药的进化轨迹，使得在DTP状态期间通过获得T790M守门基因突变和鳞状转分化产生耐药性的可能性更大。载脂蛋白B3B表达与吉非替尼耐药细胞中鳞状细胞转录因子ΔNp63的表达增加及鳞状细胞转分化相关。在吉非替尼耐药细胞中敲除p63会降低ΔNp63靶基因IL1α/β的表达，并使这些细胞对第三代EGFR抑制剂奥希替尼敏感。这些结果表明，载脂蛋白B活性通过促进DTPs中的进化和转分化来促进获得性耐药，并表明在吉非替尼耐药的肺癌中靶向ΔNp63的方法可能具有治疗益处。
