S6K1 blockade overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer

Abstract

The development of resistance to EGFR Tyrosine kinase inhibitors (TKIs) in NSCLC with activating EGFR mutations is a critical limitation of this therapy. In addition to genetic alterations such as EGFR secondary mutation causing EGFR-TKI resistance, compensatory activation of signaling pathways without interruption of genome integrity remains to be defined. In this study, we identified S6K1/MDM2 signaling axis as a novel bypass mechanism for the development of EGFR-TKI resistance. The observation of S6K1 as a candidate mechanism for resistance to EGFR TKI therapy was investigated by interrogation of public databases and a clinical cohort to establish S6K1 expression as a prognostic/predictive biomarker. The role of S6K1 in TKI resistance was determined in in vitro gain-and-loss of function studies and confirmed in subcutaneous and orthotopic mouse lung cancer models. Blockade of S6K1 by a specific inhibitor PF-4708671 synergistically enhanced the efficacy of TKI without showing toxicity. The mechanistic study showed the inhibition of EGFR caused nuclear translocation of S6K1 for binding with MDM2 in resistant cells. MDM2 is a downstream effector of S6K1-mediated TKI resistance. Taken together, we present evidence for the reversal of resistance to EGFR TKI by the addition of small molecule S6K1/MDM2 antagonists that could have clinical benefit.

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Fig. 1: p-S6K1 is elevated in a NSCLC patient with acquired resistance to TKIs.
Fig. 2: S6K1 phosphorylation levels are correlated with EGFR-TKI resistance and poor prognosis in NSCLC patients.
Fig. 3: Persistent activation of S6K1 signaling in acquired resistant non-small lung cancer cells with EGFR-TKIs treatments.
Fig. 4: S6K1 affects cell responsiveness to TKIs treatments in NSCLC cells.
Fig. 5: S6K1 inhibitor PF-4708671 enhanced TKI-induced cytotoxicity in vitro.
Fig. 6: PF-4708671 improves the efficacy of EGFR-TKIs in vivo.
Fig. 7: MDM2 is a downstream effector of S6K1-mediated TKIs resistance.

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Acknowledgements

We appreciate Jennifer Fisher Wilson (Science and Medical Writer, Thomas Jefferson University) for her help on English editing. We thank Dr. Paul Fox and Dr. Terenzi (Cleveland Clinic) for kindly providing S6K1 knockout mice tissues.

Funding

This work was supported by National Cancer Institute (R00 CA 215316, R01 CA232587, R01 CA160495), Natural Science Foundation of China (No. 81874230), Jiangsu Social Development Project (China, BE2018726), the Natural Science Foundation of Jiangsu Province (Grants No. BK20171484), the Project of Invigorating Health Care through Science, Technology, and Education (Jiangsu Provincial Medical Youth Talent QNRC2016856), the Summit of the Six Top Talents Program of Jiangsu Province (2017-WSN-179). Research reported in this publication utilized the Flow Cytometry Facility at Sidney Kimmel Cancer Center at Jefferson Health, which was supported by the NCI of the NIH (P30CA056036).

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Correspondence to Jun He.

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Shen, H., Wang, G., Li, X. et al. S6K1 blockade overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer. Oncogene (2020). https://doi.org/10.1038/s41388-020-01497-4

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