ROS诱导靶向NRAS突变黑色素瘤中代谢活性低的持久癌细胞。
ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma.
发表日期：2023 Mar 22
作者：
Ossia M Eichhoff, Corinne I Stoffel, Jan Käsler, Luzia Briker, Patrick Turko, Gergely Karsai, Nina Zila, Verena Paulitschke, Phil F Cheng, Alexander Leitner, Andrea Bileck, Nicola Zamboni, Anja Irmisch, Zsolt Balazs, Aizhan Tastanova, Susana Pascoal, Pål Johansen, Rebekka Wegmann, Julien Mena, Alaa Othman, Vasanthi S Viswanathan, Judith Wenzina, Andrea Aloia, Annalisa Saltari, Andreas Dzung, , Rudolf Aebersold, Melike Ak, Faisal S Al-Quaddoomi, Silvana I Albert, Jonas Albinus, Ilaria Alborelli, Sonali Andani, Per-Olof Attinger, Marina Bacac, Daniel Baumhoer, Beatrice Beck-Schimmer, Niko Beerenwinkel, Christian Beisel, Lara Bernasconi, Anne Bertolini, Bernd Bodenmiller, Ximena Bonilla, Lars Bosshard, Byron Calgua, Ruben Casanova, Stéphane Chevrier, Natalia Chicherova, Ricardo Coelho, Maya D'Costa, Esther Danenberg, Natalie Davidson, Monica-Andreea Drãgan, Reinhard Dummer, Stefanie Engler, Martin Erkens, Katja Eschbach, Cinzia Esposito, André Fedier, Pedro Ferreira, Joanna Ficek, Anja L Frei, Bruno Frey, Sandra Goetze, Linda Grob, Gabriele Gut, Detlef Günther, Martina Haberecker, Pirmin Haeuptle, Viola Heinzelmann-Schwarz, Sylvia Herter, Rene Holtackers, Tamara Huesser, Alexander Immer, Anja Irmisch, Francis Jacob, Andrea Jacobs, Tim M Jaeger, Katharina Jahn, Alva R James, Philip M Jermann, André Kahles, Abdullah Kahraman, Viktor H Koelzer, Werner Kuebler, Jack Kuipers, Christian P Kunze, Christian Kurzeder, Kjong-Van Lehmann, Mitchell Levesque, Ulrike Lischetti, Sebastian Lugert, Gerd Maass, Markus G Manz, Philipp Markolin, Martin Mehnert, Julien Mena, Julian M Metzler, Nicola Miglino, Emanuela S Milani, Holger Moch, Simone Muenst, Riccardo Murri, Charlotte Ky Ng, Stefan Nicolet, Marta Nowak, Monica Nunez Lopez, Patrick Ga Pedrioli, Lucas Pelkmans, Salvatore Piscuoglio, Michael Prummer, Natalie Rimmer, Mathilde Ritter, Christian Rommel, María L Rosano-González, Gunnar Rätsch, Natascha Santacroce, Jacobo Sarabia Del Castillo, Ramona Schlenker, Petra C Schwalie, Severin Schwan, Tobias Schär, Gabriela Senti, Wenguang Shao, Franziska Singer, Sujana Sivapatham, Berend Snijder, Bettina Sobottka, Vipin T Sreedharan, Stefan Stark, Daniel J Stekhoven, Tanmay Tanna, Alexandre Pa Theocharides, Tinu M Thomas, Markus Tolnay, Vinko Tosevski, Nora C Toussaint, Mustafa A Tuncel, Marina Tusup, Audrey Van Drogen, Marcus Vetter, Tatjana Vlajnic, Sandra Weber, Walter P Weber, Rebekka Wegmann, Michael Weller, Fabian Wendt, Norbert Wey, Andreas Wicki, Mattheus He Wildschut, Bernd Wollscheid, Shuqing Yu, Johanna Ziegler, Marc Zimmermann, Martin Zoche, Gregor Zuend, Michael Krauthammer, Stuart L Schreiber, Thorsten Hornemann, Martin Distel, Berend Snijder, Reinhard Dummer, Mitchell P Levesque
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
具有NRAS突变的黑色素瘤的临床管理具有挑战性。由于遗传、转录和代谢适应性引起的抵抗，靶向MAPK信号通路只对一小部分患者有益。鉴定NRAS突变黑色素瘤可靶向的易感性能有助于改善患者的治疗效果。在这里，我们使用多组学分析揭示NRAS突变的黑色素瘤细胞采用基质细胞表型具有静止代谢程序，以抵御MEK抑制所诱导的细胞压力。代谢变化提高了基线活性氧（ROS）水平，使这些细胞对ROS诱导变得高度敏感。体内异种移植实验和单细胞RNA测序证明肿瘤内异质性需要联合使用ROS诱导剂和MEK抑制剂以抑制肿瘤生长和转移。62个人类转移性黑色素瘤的外体药物灵敏度研究证实，MEK抑制剂耐药肿瘤从联合治疗中获得显著益处。最后，486个癌细胞系的氧化应激反应和翻译抑制与ROS诱导剂的敏感性相对应，独立于癌症类型。这些研究发现将转录可塑性与代谢表型联系起来，该表型可以通过ROS诱导剂来抑制黑色素瘤和其他癌症。
MEK通路抑制药物耐药NRAS突变黑色素瘤细胞的代谢重编程使其对ROS诱导变得敏感，联合MAPK通路抑制剂能够抑制肿瘤生长和转移。
©2023美国癌症研究协会。
Clinical management of melanomas with NRAS mutations is challenging. Targeting MAPK signaling is only beneficial to a small subset of patients due to resistance that arises through genetic, transcriptional, and metabolic adaptation. Identification of targetable vulnerabilities in NRAS-mutated melanoma could help improve patient treatment. Here, we used multiomics analyses to reveal that NRAS-mutated melanoma cells adopt a mesenchymal phenotype with a quiescent metabolic program to resist cellular stress induced by MEK inhibition. The metabolic alterations elevated baseline reactive oxygen species (ROS) levels, leading these cells to become highly sensitive to ROS induction. In vivo xenograft experiments and single-cell RNA sequencing demonstrated that intratumor heterogeneity necessitates the combination of a ROS inducer and a MEK inhibitor to inhibit both tumor growth and metastasis. Ex vivo pharmacoscopy of 62 human metastatic melanomas confirmed that MEK inhibitor-resistant tumors significantly benefited from the combination therapy. Finally, oxidative stress response and translational suppression corresponded with ROS-inducer sensitivity in 486 cancer cell lines, independent of cancer type. These findings link transcriptional plasticity to a metabolic phenotype that can be inhibited by ROS inducers in melanoma and other cancers.Metabolic reprogramming in drug-resistant NRAS-mutated melanoma cells confers sensitivity to ROS induction, which suppresses tumor growth and metastasis in combination with MAPK pathway inhibitors.©2023 American Association for Cancer Research.