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Induction of SREBP1 degradation coupled with suppression of SREBP1-mediated lipogenesis impacts the response of EGFR mutant NSCLC cells to osimertinib

Oncogene volume 40, pages 6653–6665 (2021)Cite this article

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Abstract

Emergence of acquired resistance to osimertinib (AZD9291), the first-approved third-generation EGFR inhibitor that selectively and irreversibly inhibits the activating EGFR mutations and the resistant T790M mutation, is a giant and urgent clinical challenge. Fully understanding the biology underlying the response of EGFR mutant non-small cell lung cancer (NSCLC) to osimertinib is the foundation for development of mechanism-driven strategies to overcome acquired resistance to osimertinib or other third-generation EGFR inhibitors. This study focused on tackling this important issue by elucidating the critical role of sterol regulatory element-binding protein 1 (SREBP1) degradation in conferring the response of EGFR mutant NSCLC cells to osimertinib and by validating the strategy via directly targeting SREBP1 for overcoming osimertinib acquired resistance. Osimertinib facilitated degradation of the mature form of SREBP1 (mSREBP1) in a GSK3/FBXW7-dependent manner and reduced protein levels of its regulated genes in EGFR-mutant NSCLC cells/tumors accompanied with suppression of lipogenesis. Once resistant, EGFR-mutant NSCLC cell lines possessed elevated levels of mSREBP1, which were resistant to osimertinib modulation. Both genetic and pharmacological inhibition of SREBP1 sensitized osimertinib-resistant cells and tumors to osimertinib primarily through enhancing Bim-dependent induction of apoptosis, whereas enforced expression of ectopic SREBP1 in sensitive EGFR-mutant NSCLC cells compromised osimertinib’s cell-killing effects. Collectively, we have demonstrated a novel connection between osimertinib and SREBP1 degradation and its impact on the response of EGFR mutant NSCLC cells to osimertinib and suggested an effective strategy for overcoming acquired resistance to osimertinib, and possibly other EGFR inhibitors, via targeting SREBP1.

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Fig. 1: Osimertinib inhibits mTORC2 signaling and decreases mSREBP1 levels in EGFRm NSCLC cells accompanied with reduction of ACC and FASN.
Fig. 2: Osimertinib effectively suppresses SREBP1-regulated lipid metabolism in EGFRm NSCLC cells.
Fig. 3: Osimertinib reduces mSREBP1 levels through facilitating GSK3/FBXW7-mediated mSREBP1 degradation.
Fig. 4: EGFRm NSCLC cells and tissues with acquired resistance to osimertinib or other EGFR-TKIs possess elevated levels of mSREBP1 and/or FASN, which are resistant to osimertinib modulation, and enforced expression of ectopic in sensitive EGFRm NSCLC cells confers resistance to osimertinib.
Fig. 5: Genetic knockdown of SREBP1 reverses osimertinib resistance in vitro and in vivo.
Fig. 6: Chemical inhibition of SREBP1 combined with osimertinib synergistically decreases survival with enhanced apoptosis of osimertinib-resistant NSCLC cells and overcomes osimertinib resistance in vivo.
Fig. 7: Osimertinib combined with SREBP1 inhibition enhances Bim and Mcl-1 levels and augments Bim-dependent apoptosis in osimertinib-resistant cells.

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Acknowledgements

We are thankful to Dr. Dongsheng Wang and Mr. Guojing Zhang in our department for helping us with animal experiments, to Dr. Teng Wang and Dr. Dong Hua (Affiliated Hospital of Jiangnan University) for providing us with clinical samples, to Dr. Peng Zhang (Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T.) for staining the patients’ samples, and to Drs. Deliang Guo and Wenyi Wei for providing some shRNAs. We are also grateful to Dr. Anthea Hammond in our department for editing the manuscript. This work was supported by the NIH/NCI R01 CA223220 (to S-YS), R01 CA245386 (to S-YS), UG1 CA233259 (to SSR) and lung cancer SPORE P50 CA217691 DRP award (to S-YS) and Emory University Winship Cancer Institute lung cancer pilot funds (to S-YS). DY is a visiting medical student participating in the Xiangya-Emory Visiting Medical Student Program. SSR, TKO, and S-YS are Georgia Research Alliance Distinguished Cancer Scientists.

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Authors and Affiliations

  1. Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA

    Zhen Chen, Danlei Yu, Suresh S. Ramalingam & Shi-Yong Sun

  2. Department of Medicine, University of Pittsburgh and Hillman Cancer Center, Pittsburgh, PA, USA

    Taofeek K. Owonikoko

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  1. Zhen Chen
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Contributions

Conceptualization: S-YS, ZC, TKO, and SSR. Investigation: ZC and DY. Methodology: ZC and S-YS. Writing/Original draft: ZC and S-YS. Funding acquisition: S-YS and SSR. Supervision: TKO, SSR, and S-YS.

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Correspondence to Shi-Yong Sun.

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Competing interests

SSR is on consulting/advisory board for AstraZeneca, Amgen, BMS, Merck, Roche, Tesaro and Amgen. TKO is on consulting/advisory board for Novartis, Celgene, Lilly, Sandoz, Abbvie, Eisai, Takeda, Bristol-Myers Squibb, MedImmune, Amgen, AstraZeneca and Boehringer Ingelheim. Other authors declare that they have no conflict of interest.

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Chen, Z., Yu, D., Owonikoko, T.K. et al. Induction of SREBP1 degradation coupled with suppression of SREBP1-mediated lipogenesis impacts the response of EGFR mutant NSCLC cells to osimertinib. Oncogene 40, 6653–6665 (2021). https://doi.org/10.1038/s41388-021-02057-0

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