rupitasertib (DIACC3010)

To block pS6, we paired dasatinib with the S6K/AKT inhibitor M2698, which led to a marked reduction in pS6 in IDHm ICC cell lines and patient-derived organoids in vitro and substantial growth inhibition in ICC patient-derived xenografts in vivo. Together, these results elucidated the mechanism of action of dasatinib in IDHm ICC, revealed a signaling complex regulating S6K phosphorylation independent of mTOR, suggested markers for dasatinib sensitivity, and described a combination therapy for IDHm ICC that may be actionable in the clinic.

Of the 21 HER2-negative PDX models, DIACC3010 significantly inhibited the growth of 38%. Altogether, these results provide a path forward to validate the potential biomarkers of DIACC3010 sensitivity in GC and support clinical evaluation of DIACC3010 monotherapy and combination with trastuzumab in patients with HER2- negative and positive advanced GCs, respectively.

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. 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). 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.

Our data elucidate the incidence and mechanisms of psychiatric AEs in patients treated with PI3K/AKT/mTOR inhibitors and emphasize the need for careful monitoring.

M2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance. Trial registration ClinicalTrials.gov, NCT01971515. Registered October 23, 2013.