Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors-Reference-Cited by-同舟云学术

Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors

Published:2023-09-08 Issue:6662 Volume:381 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Lv Xiangdong¹²³^ORCID,Lu Xuan¹²³^ORCID,Cao Jin¹²³^ORCID,Luo Qin¹²³,Ding Yao¹²³,Peng Fanglue¹²³^ORCID,Pataer Apar⁴^ORCID,Lu Dong¹⁵⁶^ORCID,Han Dong¹²³^ORCID,Malmberg Eric¹²³^ORCID,Chan Doug W.¹²³^ORCID,Wang Xiaoran¹²³^ORCID,Savage Sara R.²³⁷^ORCID,Mao Sufeng¹²³^ORCID,Yu Jingjing¹²³,Peng Fei¹⁸^ORCID,Yan Liang⁹^ORCID,Meng Huan¹^ORCID,Maneix Laure¹¹⁰^ORCID,Han Yumin¹²³,Chen Yiwen¹¹^ORCID,Yao Wantong¹²,Chang Eric C.¹²³^ORCID,Catic Andre¹¹⁰^ORCID,Lin Xia¹³,Miles George²³⁷,Huang Pengxiang¹,Sun Zheng¹⁸^ORCID,Burt Bryan¹⁴,Wang Huamin¹⁵,Wang Jin¹⁵⁶^ORCID,Yao Qizhi Cathy¹³^ORCID,Zhang Bing²³⁷^ORCID,Roth Jack A.⁴^ORCID,O’Malley Bert W.¹^ORCID,Ellis Matthew J.²³¹⁶^ORCID,Rimawi Mothaffar F.²³^ORCID,Ying Haoqiang⁹^ORCID,Chen Xi¹²³^ORCID

Affiliation:

1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

2. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.

3. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.

4. Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

5. Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA.

6. Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA.

7. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

8. Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX 77030, USA.

9. Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

10. Huffington Center on Aging, Baylor College of Medicine, USA.

11. Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

12. Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

13. Division of Surgical Oncology, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.

14. Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.

15. Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

16. Early Oncology, Oncology R&D, AstraZeneca, Gaithersburg, MD, USA.

Abstract

Despite substantial advances in targeting mutant KRAS, tumor resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report proteostasis reprogramming as a key convergence point of multiple KRASi-resistance mechanisms. Inactivation of oncogenic KRAS down-regulated both the heat shock response and the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1α was selectively reactivated in an ER stress–independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1α protein stability through extracellular signal–regulated kinase (ERK)–dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In KRASi-resistant tumors, both reactivated ERK and hyperactivated AKT restored IRE1α phosphorylation and stability. Suppression of IRE1α overcame resistance to KRASi. This study reveals a druggable mechanism that leads to proteostasis reprogramming and facilitates KRASi resistance.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/science.abn4180

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