Abstract 1525: SY-1365, a selective CDK7 inhibitor, exhibits potent antitumor activity against ovarian cancer models in vitro and in vivo
Authors: Konstantinopoulos Panagiotis A. , Hodgson Graeme , Rajagopal Nisha , Johannessen Liv , Liu Joyce F. , Kirschmeier Paul T. , Zhou Shan , Tran Cam Anh , Orlando David , Fritz Christian , Tomaso Emmanuelle di , Matulonis Ursula A. 
Published: August 2018

Introduction: CDK7, a key regulator of transcription and cell cycle progression, has been implicated in the pathogenesis of ovarian carcinoma. SY-1365, a potent and selective inhibitor of CDK7, was developed to exploit tumor dependencies driven by CDK7 and is in phase 1 clinical development. Here we report, for the first time, on the activity of SY-1365 in preclinical models of ovarian carcinoma and on potential biomarkers of SY-1365 response.

Methods: SY-1365 growth rate inhibition (GR) curves were determined in 314 solid tumor cell lines, including 22 ovarian carcinoma lines. Cell lines were clustered into cytotoxic and cytostatic response groups and assessed for RNA expression to identify markers associated with SY-1365 sensitivity. In vivo, SY-1365 activity was evaluated at the maximum tolerated dose in 17 independent ovarian PDX models derived from heavily pretreated patients; a signal-finding design was used in which tumor growth in SY-1365 treated mice (n=2-3 per PDX model) was compared to vehicle-treated mice or historical growth in untreated mice.

Results: SY-1365 induced cytotoxicity (GR &lt;0) in 61% (190/314) of all tumor lines at &lt;50nM. In ovarian carcinoma lines, 36% (8/22) were cytotoxic at &lt;50nM, with deep responses (GRmax &lt; -0.5) seen in 23% (5/22). Lower expression of BCL2L1, which encodes the mitochondrial apoptosis antagonist BCLXL, was the most predictive marker of sensitivity across all lines (accuracy = 70%; FDR=0.006). Reasoning that low BCL2L1 may be a marker of dependence on other mitochondrial apoptosis antagonists (MCL1 and/or BCL2) for survival, we evaluated expression of BCL2, BCLXL, and MCL1 protein at baseline and post-SY-1365 treatment in ovarian carcinoma lines. As with BCL2L1 RNA, BCLXL expression was lower at baseline in cytotoxic- versus cytostatic-responsive lines. In addition, SY-1365 induced MCL1 downregulation in cytotoxic, but not in cytostatic lines. In vivo, SY-1365 induced responses in 52% (9/17) of ovarian carcinoma PDX models. Of the 9 responders, 2 exhibited 40-60% tumor growth inhibition (TGI), 7 exhibited ≥ 100% TGI. As in cell lines, low BCLXL, in combination with low BCL2, was associated with SY-1365 response in PDXs. In addition, 7/9 responsive models had alterations in the RB signaling pathway including loss of RB1 expression (n=3), high CCNE1 expression (n=3), or CDKN2A loss (n=1).

Conclusions: SY-1365 induces cytotoxicity in ovarian carcinoma cell lines and induces robust responses in heavily pretreated (including PARP-inhibitor and platinum-resistant) ovarian PDX models. Alterations in expression of mitochondrial apoptosis antagonists and RB pathway regulators are associated with SY-1365 response and support exploration of these as predictive biomarkers of SY-1365 clinical activity in ovarian carcinoma. SY-1365 is currently being assessed in a phase 1 trial in adult patients with advanced solid tumors (NCT03134638).

Citation Format: Panagiotis A. Konstantinopoulos, Graeme Hodgson, Nisha Rajagopal, Liv Johannessen, Joyce F. Liu, Paul T. Kirschmeier, Shan Zhou, Cam Anh Tran, David Orlando, Christian Fritz, Emmanuelle di Tomaso, Ursula A. Matulonis. SY-1365, a selective CDK7 inhibitor, exhibits potent antitumor activity against ovarian cancer models in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1525.