Abstract 428: Therapeutic potential of the novel SHP2 degrader, SHP2-D26, alone or in combination, in the treatment of lung cancer

Abstract

Abstract Src homology 2 domain-containing phosphatase 2 (SHP2) functions as a protein tyrosine phosphatase and plays a critical role in the full activation of the Ras-MAPK signaling pathway downstream of cell surface tyrosine receptors (e.g., EGFR), which are frequently amplified or mutationally activated in human cancer. Therefore, SHP2 has emerged as an attractive therapeutic target for human cancers and other human diseases. While some allosteric inhibitors that are being tested in clinical trials, a few SHP2 degraders have been developed recently. However, their activities in human lung cancer have not been tested. The current 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 cell (NSCLC). Most of tested NSCLC cell lines (12/14) were insensitive to the control small molecule SHP2 inhibitor with IC50s of far over 10 μM. However, all these cell lines responded to D26 with IC50s of < 8 μM. A few cell lines (4/14; e.g. HCC827, PC-9, H1792 and H1648) were much more sensitive than others with IC50s of < 3 μM. There was no clear association between basal levels of SHP2 and cell sensitivities to D26. Interestingly, D26 rapidly and potently decreased SHP2 levels in all the tested cell lines in a sustained way regardless cell sensitivities to D26, suggesting that there may be additional factors that impact cell response to D26. We noted that suppression of p70S6/S6, but not ERK1/2, was associated with cell responses to D26, warranting further study in this direction. In the sensitive cell lines, D26 effectively increased Bim levels while decreasing Mcl-1 levels likely through modulating their stability accompanied with induction of apoptosis. These events are all important for D26 to induce apoptosis. When combined with the third generation EGFR, osimertinib (AZD9291), synergistic effects on decreasing the survival of different osimertinib-resistant cell lines were observed. Moreover, the combination enhanced induction of apoptosis in these osimertinib-resistant cells. Although D26 alone exerted moderate effect on inhibiting the growth of NSCLC xenografts, the combination of osimertinib with D26 very effectively inhibited the growth of osimertinib-resistant xenografts, suggesting promising efficacy in overcoming acquired resistance to osimertinib. Our findings thus warrant further evaluation of the potential of D26 in overcoming acquired resistance to osimertinib in clinic. Citation Format: Yunful Deng, Guangzhi Ma, Karin A. Vallega, Dongsheng Wang, Mingliang Wang, Changwei Wang, Shaomeng Wang, Suresh S. Ramalingam, Shi-Yong Sun. Therapeutic potential of the novel SHP2 degrader, SHP2-D26, alone or in combination, in the treatment of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 428.