Abstract B043: Targeting dual CDK9 and KRASG12D selective inhibition as a novel combination therapy in pancreatic ductal adenocarcinoma
Michela Cadarso, Paulina Esguerra, Lauryn Flannagan, Md Shahadat Hossan, Jeremy D. KratzAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer related mortality with a critical need for novel therapeutic strategies. Cyclin dependent kinase 9 (CDK9) is a transcriptional regulator of RNA polymerase II (Pol II) by phosphorylation of serine residues on the C terminal domain of the positive transcription elongation factor (pTEF). Tri-complex RAS(ON) inhibitors are emerging in clinical practice including daraxonrasib (RMC-6236) and zoldonrasib (RMC-9805), a KRASG12D selective inhibitor with favorable toxicity. Here, we examine a patient-derived cancer organoid (PCO) model that is MYC-amplified to assess the activity of combining CDK9 inhibition (SLS009) with tricomplex RAS (ON inhibitors) studying both RMC-6236 and RMC-9805.
Methods:
PCOs were assayed using medium throughput 96 well assay (Ibidi, Inc) for high content imaging (Cytation 5). Single and dual agent activity of SLS009 (200nM) and RMC-6236 (100nM) was assessed with an assay endpoint of 72 hours. RMC-6236 was treated continuously, while SLS009 was removed after 24 hours to mimic in vivo pharmacokinetics. Initial response was assessed by normalized change in PCO area after 72 hours. Subsequent viability staining was performed for apoptosis (Caspase-3/7) and necrosis (TOPRO3). Statistical analysis was conducted using one-way ANOVA followed by Tukey’s post hoc test to compare the mean percentage of area stained between treatment groups. SLS009 was assessed for single agent activity to compared sensitivity across resistance to RMC-9805. Western blot analysis was performed for critical resistance mechanisms including c-MYC and MCL-1 using a LICOR M Odyssey system.
Results:
SLS009 in combination with RMC-6236 significantly augments the induction of apoptosis and necrosis compared to single agent activity. Apoptosis staining as assessed for % area positive for the combination group increased to 36.49% relative to the negative control (6.965%, p<0.001), and in comparison to single agent SLS009 (17.88%, p<0.001) and RMC-6236 (2.781%, p=0.0086). Necrosis staining as assessed by % area positive for the combination group increased to 30.62% relative to the negative control (6.723%, p<0.001), in comparison to single agent SLS009 (14.51%, p<0.001) and RMC-6236 (2.702%, p=0.0044). Western blots of protein collected from naïve PCO and RMC-9805 resistant PCO treated with SLS009 for 24 hours showed potent decrease in c-MYC and MCL-1 activity. SLS009 was found to have improved potency as single agent IC50 (65.06 +/- 14.47nM SEM) in the RMC-9805 resistant PCO as compared to the naïve line (96.78 +/- 14.70nM SEM).
Discussion:
The combination of transcriptional targeting with SLS009 in combination with tricomplex RAS (ON) inhibition significantly augments the induction of apoptosis and necrosis. Ongoing work includes evaluating biomarkers predictive of this response and activity across heterotopic in vivo models.
Citation Format:
Michela Cadarso, Paulina Esguerra, Lauryn Flannagan, Md Shahadat Hossan, Jeremy D. Kratz. Targeting dual CDK9 and KRASG12D selective inhibition as a novel combination therapy in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B043.