Abstract 4477: DIACC3010, optimized inhibitor of S6 kinase, combined with endocrine therapy, has potent antitumor activity in treatment-resistant ER-positive HER2-negative metastatic breast cancer
Authors: Navarro Christel , Tsimberidou Apostolia Maria , Bougeret Cecile , Borghi Elsa , Bridon Dominique , Sicard Helene 
Published: April 2023

Abstract
Background: Ribosomal protein S6 kinase (S6K) is a key regulator of estrogen receptor (ER) function, and its high expression is associated with poor clinical outcomes in breast cancer (BC). Recent data have demonstrated that S6K is involved in resistance to CDK4/6 inhibitors in metastatic BC (MBC). DIACC3010 (formerly M2698) is an oral brain-penetrant potent inhibitor of S6K. By design, DIACC3010 also selectively inhibits AKT1 and AKT3, while sparing AKT2. DIACC3010 was previously evaluated in a phase 1 trial (NCT01971515). We performed exploratory correlative analyses of the phase 1 trial in ER+ HER2-negative MBC patients in addition to nonclinical experiments to evaluate its role in the CDK4/6 and endocrine therapy (ET) resistant setting.
Methods: DIACC3010 was evaluated as monotherapy, or combined with either trastuzumab or tamoxifen, in a multicenter phase 1 trial that accrued 101 patients with advanced/refractory solid tumors (Tsimberidou et al, J Hematol Oncol 2021 14(1):127). The current analysis focused on patients with ER+ HER2-negative MBC and aimed to explore the efficacy of DIACC3010 according to ESR1 mutational status. DIACC3010 was also evaluated in tamoxifen resistant patient-derived xenograft (PDX) mouse models, both alone and combined with tamoxifen.
Results: Twenty patients were evaluable at baseline for their tumor mutational status and included in the analysis. Median age was 60 years and median number of prior lines of therapy was 5.5. Twelve of 20 (60%) patients had received prior treatment with CDK4/6 inhibitors. Nine of 20 patients (45%) had ESR1 mutations, of whom 4 had received CDK4/6 inhibitor. Median progression free survival was 5.6 months in patients with ESR1 mutations, and 2.6 months in patients with ESR1 wild-type tumors. Among the 13 ER+ BC PDX models evaluated, 10 provided interpretable results and 4 were found resistant to tamoxifen. The combination of DIACC3010 and tamoxifen significantly reduced tumor growth in 6/10 (60%) of all PDX models, and in 4/4 (100%) of the tamoxifen-resistant PDX models.
Conclusions: Exploratory analyses from the phase 1 trial, along with nonclinical efficacy in PDX models, demonstrate that DIACC3010 may have antitumor activity in MBC patients with ET resistance. Experiments are underway to assess nonclinical efficacy of DIACC3010 combination with elacestrant or CDK4/6 inhibitors in various models of ER+ MBC, including ET resistant.
Citation Format: Christel Navarro, Apostolia Maria Tsimberidou, Cecile Bougeret, Elsa Borghi, Dominique Bridon, Helene Sicard. DIACC3010, optimized inhibitor of S6 kinase, combined with endocrine therapy, has potent antitumor activity in treatment-resistant ER-positive HER2-negative metastatic breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4477.