Abstract 4732: CDK4/6 inhibition with lerociclib (G1T38) enhances response to PI3K or ERK inhibitors in high-throughput, ex vivo pancreatic PDX screens
Authors: Dai Bingbing , Freed Daniel M. , Sorrentino Jessica A. , Augustine Jithesh Jose , Hughes Tara G. , Kang Ya'an , Roberts Patrick J. , Fleming Jason B. , Kim Michael P. 
Published: August 2019

Introduction: In pancreatic ductal adenocarcinoma (PDAC), mutations in KRAS and deletion or promoter methylation of the CDKN2A gene - resulting in deregulation of the p16/CDK4/CDK6/RB axis - each occur in over 90% of cases. Therefore, combination therapy approaches targeting KRAS effectors and CDK4/6 may be a promising treatment strategy in a majority of PDAC patients. Lerociclib (G1T38) is an oral and selective CDK4/6 inhibitor in clinical development as a potential backbone therapy for multiple combination regimens in cancer. Here, we used a powerful and reliable ex vivo drug screening platform, the live tissue sensitivity assay (LTSA), to evaluate the ability of lerociclib to synergize with inhibitors of KRAS effectors across a panel of 24 well-characterized PDAC patient-derived xenografts (PDXs).

Methods: PDX tumors were sectioned into uniform tissue slices at 200 µm thickness and arrayed in 96-well plates. For each PDX model, tumor tissue slices were treated with 0.3 µM, 1 µM, and 3 µM of lerociclib, alone and in combination with identical concentrations of a PI3K (pictilisib), mTOR (AZD2014), MEK (trametinib), ERK (ulixertinib), BRAF (vemurafenib) or EGFR (erlotinib) inhibitor for 72 hours. The viabilities of individual tissue slices were measured with PrestoBlue® reagent. A quantitative drug response analysis approach was implemented in which “responder” PDXs were defined as those exhibiting a statistically significant reduction in area under the dose-response curve (AUC) for the combination treatment compared to the most efficacious single agent. Statistical significance was defined as p &lt; 0.05 using Student’s t-test.

Results: Treatment of 24 PDAC PDXs using the LTSA revealed a range of sensitivities to each inhibitor as a single agent. When KRAS effectors and CDK4/6 were inhibited in tandem, statistically significant (p &lt; 0.05) enhancements of efficacy were observed when lerociclib was added to pictilisib (21% of PDX models tested), ulixertinib (15%), vemurafenib (10%), erlotinib (5%), trametinib (4%), or AZD2014 (4%). These ex vivo data narrowed the focus of follow-up in vivo work; studies of PDX models in mice treated with lerociclib +/- pictilisib or ulixertinib are ongoing to validate these results. Moreover, differential gene expression and mutational analysis for responders versus non-responders identified through the PDAC PDX LTSA platform are underway, to elucidate molecular factors that predict tumor response or enrich for populations that are sensitive to CDK4/6 and PI3K/ERK inhibitors.

Conclusion: The LTSA platform was used to evaluate drug combinations in viable, PDX tumor tissue. We found that lerociclib significantly enhances the response to PI3K or ERK inhibition in a substantial proportion of the tested PDAC PDXs as measured by AUC analysis in the LTSA platform, supporting future clinical evaluation of these combinations.

Citation Format: Bingbing Dai, Daniel M. Freed, Jessica A. Sorrentino, Jithesh Jose Augustine, Tara G. Hughes, Ya'an Kang, Patrick J. Roberts, Jason B. Fleming, Michael P. Kim. CDK4/6 inhibition with lerociclib (G1T38) enhances response to PI3K or ERK inhibitors in high-throughput, ex vivo pancreatic PDX screens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4732.