MYC upstream region orchestrates resistance to PI3K inhibitors in cancer cells through FOXO3a-mediated autophagic adaptation

IF 6.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2024-09-22 DOI:10.1038/s41388-024-03170-6

Rosa Bordone, Devon Michael Ivy, Rodrigo D’Amico, Martina Barba, Miriam Gaggianesi, Fiorella Di Pastena, Bianca Cesaro, Francesca Bufalieri, Alessio Balzerano, Enrico De Smaele, Giuseppe Giannini, Lucia Di Marcotullio, Alessandro Fatica, Giorgio Stassi, Laura Di Magno, Sonia Coni, Gianluca Canettieri

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引用次数: 0

Abstract

The MYC oncogene is frequently overexpressed in tumors and inhibition of its translation is considered an attractive therapeutic opportunity. Despite numerous reports proposing an internal ribosome entry site (IRES) within the MYC Upstream Region (MYC UR) to sustain MYC translation during cellular stress or chemotherapy, conflicting evidence remains regarding the validity of such a mechanism. Through comprehensive investigations in MYC-driven Colorectal Cancer (CRC) and Burkitt Lymphoma (BL) cells, we demonstrate that MYC UR does not facilitate cap-independent translation, but instead orchestrates resistance to PI3K inhibitors. Genomic deletion of MYC UR neither impacts MYC protein levels nor viability in CRC cells, either untreated or exposed to cellular stress. However, in response to PI3K inhibitors, MYC UR drives a FOXO3a-dependent transcriptional upregulation of MYC, conferring drug resistance. This resistance is mediated by enhanced autophagic flux, governed by MYC, and blockade of autophagy sensitizes CRC cells to PI3K inhibition in vitro and in vivo. Remarkably, BL cells lacking the translocation of MYC UR exhibit sensitivity to PI3K inhibitors, whereas MYC UR-translocated cells respond to these drugs only when autophagy is inhibited. These findings challenge previous notions regarding IRES-mediated translation and highlight a promising strategy to overcome resistance to PI3K inhibitors in MYC-driven malignancies, offering potential clinical implications for CRC and BL treatment.

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MYC 上游区域通过 FOXO3a 介导的自噬适应，协调癌细胞对 PI3K 抑制剂的抗性。

MYC 致癌基因经常在肿瘤中过度表达，抑制其翻译被认为是一个有吸引力的治疗机会。尽管有许多报道称 MYC 上游区（MYC UR）内有一个内部核糖体进入位点（IRES），可在细胞应激或化疗期间维持 MYC 的翻译，但关于这种机制的有效性仍存在相互矛盾的证据。通过对 MYC 驱动的结直肠癌（CRC）和伯基特淋巴瘤（BL）细胞进行全面研究，我们证明 MYC UR 并不能促进不依赖帽子的翻译，反而会协调对 PI3K 抑制剂的抗性。基因组缺失 MYC UR 既不会影响 MYC 蛋白水平，也不会影响未经处理或暴露于细胞压力下的 CRC 细胞的活力。然而，在对 PI3K 抑制剂做出反应时，MYC UR 会驱动 MYC 的 FOXO3a 依赖性转录上调，从而产生耐药性。这种耐药性是由 MYC 主导的自噬通量增强介导的，阻断自噬可使 CRC 细胞在体外和体内对 PI3K 抑制剂敏感。值得注意的是，缺乏 MYC UR 转位的 BL 细胞对 PI3K 抑制剂表现出敏感性，而 MYC UR 转位的细胞只有在自噬受到抑制时才会对这些药物产生反应。这些发现挑战了以前关于IRES介导翻译的观点，并强调了在MYC驱动的恶性肿瘤中克服对PI3K抑制剂耐药性的一种有希望的策略，为CRC和BL的治疗提供了潜在的临床意义。针对 BKM120，MYC（UR）的上游区域通过 FOXO3a 增强了 MYC 的表达，导致自噬通量增加并对 PI3K 抑制剂产生抗性（左图）。药物阻断自噬（中）或在 BL 中缺乏转位的 MYC UR 和 MYC CDS（右）可克服耐药性并诱导细胞死亡。图片在 BioRender 中创建。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.