Abstract 826: Combination of CDK4/6 and CDK2/4/6 inhibitors with novel biguanides for pancreatic cancer treatment
Authors: Samantha A. Melendrez, Mario Morales Martinez, Eduardo Mauricio Gonzalez, Gang Deng, Timothy Donahue, Michael Jung, Jaydutt V. Vadgama, Richard Pietras, Diana C. Marquez-Garban
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinomas (PDAC) is a leading cause of cancer mortality in the U.S. Men and women of African ancestry have the highest incidence and mortality rates as compared to other racial or ethnic groups. African American (AA) patients present at younger ages, with more advanced disease stage, and the least access to surgical and chemotherapeutic interventions. Risk factors include diabetes mellitus type 2 (DM2), obesity, tobacco use, age, race/ancestry, and genetic mutations. Cytotoxic chemotherapy remains a first-line treatment for many PDAC patients since current therapies are often ineffective, necessitating alternative strategies. KRAS is mutated in about 90% of PDAC cases and is essential for initiating and maintaining PDAC growth. Further, a second key genetic event in PDAC involves deletion or silencing of the CDKN2A tumor-suppressor gene that encodes p16INK4A which in turn inhibits cyclin-dependent kinases CDK4 and CDK6 and complements KRAS activation in promoting PDAC. Of note, independent epidemiologic reports show that DM2 patients treated with the biguanide, metformin, a common medication used to treat DM2, have a reduced risk of PDAC and improved survival rates among those who develop PDAC. The current study investigates the hypothesis that combination of new, more potent biguanide analogues with CDK 4/6 and CDK2/4/6 inhibitors could improve treatment outcomes for PDAC. Our work involved the assessment of a newly-designed biguanide analogue termed JD006, alone and combined with selected CDK 4/6 inhibitors (abemaciclib or ribociclib) or CDK2/4/6 inhibitor PF-0687300, on growth of human PDAC cells (Panc-1, Panc 02.03, CFPac-1) in vitro. Cell proliferation assays and immunoblot analyses were used to assess effects of treatments. Combined therapy with JD006 plus CDK 4/6 or CDK2/4/6 inhibitors significantly reduced PDAC cell proliferation (P&amp;lt;0.01); with evidence of an additive effect. Immunoblots revealed enhanced inhibition of cell cycle-related proteins and AKT/mTOR downstream signaling with combination treatment with JD006 and ribociclib, abemaciclib or PF-0687300. In conclusion, combinations of JD006 with CDK 4/6, CDK2/4/6 inhibitors appears to effectively target multiple molecular pathways, suggesting a potential new approach for PDAC treatment. Further studies are needed to compare response to treatment and molecular signatures in preclinical models from patients of different ancestry. Better understanding of these biological differences may help reduce health disparities in patients diagnosed with PDAC. [Funded by NCI 5R21CA176337; NCI U54CA143930, UCLA JCCC Breast Cancer Award, CBCRP B27IB3869, Hickey Foundation] Citation Format: Samantha A. Melendrez, Mario Morales Martinez, Eduardo Mauricio Gonzalez, Gang Deng, Timothy Donahue, Michael Jung, Jaydutt V. Vadgama, Richard Pietras, Diana C. Marquez-Garban. Combination of CDK4/6 and CDK2/4/6 inhibitors with novel biguanides for pancreatic cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 826.