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Therapeutic efficacy of the novel SHP2 degrader SHP2-D26, alone or in combination, against lung cancer is associated with modulation of p70S6K/S6, Bim and Mcl-1

A Correction to this article was published on 10 May 2022

This article has been updated

Abstract

SHP2, a protein tyrosine phosphatase, plays a critical role in fully activating oncogenic signaling pathways such as Ras/MAPK downstream of cell surface tyrosine receptors (e.g., EGFR), which are often activated in human cancers, and thus has emerged as an attractive cancer therapeutic target. This study focused on evaluating the therapeutic potential of the novel SHP2 degrader, SHP2-D26 (D26), either alone or in combination, against non-small cell lung cancer (NSCLC) cells. While all tested NSCLC cell lines responded to D26 with IC50s of < 8 μM, a few cell lines (4/14) were much more sensitive than others with IC50s of ≤ 4 μM. There was no clear association between basal levels of SHP2 and cell sensitivities to D26. Moreover, D26 rapidly and potently decreased SHP2 levels in different NSCLC cell lines in a sustained way regardless of cell sensitivities to D26, suggesting that additional factors may impact cell response to D26. We noted that suppression of p70S6K/S6, but not ERK1/2, was associated with cell responses to D26. In the sensitive cell lines, D26 effectively increased Bim levels while decreasing Mcl-1 levels accompanied with the induction of apoptosis. When combined with the third generation EGFR inhibitor, osimertinib (AZD9291), synergistic effects on decreasing the survival of different osimertinib-resistant cell lines were observed with enhanced induction of apoptosis. Although D26 alone exerted moderate inhibition of the growth of NSCLC xenografts, the combination of osimertinib and D26 effectively inhibited the growth of osimertinib-resistant xenografts, suggesting promising efficacy in overcoming acquired resistance to osimertinib.

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Fig. 1: D26 effectively degrades SHP2 accompanied with suppression of NSCLC cells.
Fig. 2: D26 consistently decreases p-S6 levels, but has varied effects on p-ERK1/2 and p-Akt in NSCLC cell lines.
Fig. 3: D26 induces apoptosis with modulation of both Bim and Mcl-1 in NSCLC cell lines.
Fig. 4: D26 modulates Bim and Mcl-1 stability that contributes to induction of apoptosis in NSCLC cells.
Fig. 5: D26 inhibits the growth of PC-9 xenografts with SHP2 degradation, modulation of downstream protein levels and induction of apoptosis in vivo.
Fig. 6: The combination of D26 and osimertinib synergistically decreases survival and suppresses colony formation and growth of osimertinib resistant EGFRm NSCLC cells with enhanced induction of apoptosis and release of Cyt C and Smac from mitochondria.
Fig. 7: D26 combined with osimertinib effectively and safely inhibits the growth of PC-9/AR xenografts with enhanced induction of apoptosis in vivo.

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All data presented have been included in this report.

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Acknowledgements

We thank Dr. A. Hammond in our department for editing the manuscript. SSR and S-YS are Georgia Research Alliance Distinguished Cancer Scientists. This study was supported by Emory University Winship Cancer Institute lung cancer pilot fund (to S-YS).

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Conceptualization: YD, SW, SSR, and SYS. Investigation: YD, GM, KAV, DW, MW, and CW. Methodology: YD, GM, KAV, DW, MW, CW and SYS. Writing/Original Draft: YD and SYS. Review/Editing: GM, KAV, DW, MW, CW, SW, and SSR. Funding Acquisition: SSR and SYS. Supervision: SW and SYS

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Correspondence to Shi-Yong Sun.

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Competing interests

SSR is on consulting/advisory board for AstraZeneca, BMS, Merck, Roche, Tesaro and Amgen. The University of Michigan has filed a patent application on SHP2-D26 and its analogs. SW and MW are co-inventors of the patent application, which has been licensed by Roivant Sciences and Proteovant Therapeutics Inc. SW is a paid consultant to Roivant Sciences and Proteovant Therapeutics. The University of Michigan has received a research contract for which SW serves as the principal investigator. Other authors disclose that they have no potential conflicts of interest.

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Deng, Y., Ma, G., Vallega, K.A. et al. Therapeutic efficacy of the novel SHP2 degrader SHP2-D26, alone or in combination, against lung cancer is associated with modulation of p70S6K/S6, Bim and Mcl-1. Cancer Gene Ther 29, 1558–1569 (2022). https://doi.org/10.1038/s41417-022-00472-3

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