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CDK9-Specific PROTAC 2 Treatment Sensitizes Pancreatic Cancer Cells to Navitoclax

AJAS · 2025 Biomedical and Health Sciences (inferred)

Pranavi Prakash · Nebraska Academy of Sciences

Overview

Pancreatic Cancer (PC) has the highest mortality rate of all major cancers. PC is currently the third leading cause of cancer-related death, with a 5-year survival rate of 13% in the United States. Cyclin-dependent kinase 9 (CDK9) and anti-apoptotic pathway-specific Bcl-2 family members (Mcl-1, Bcl-xL, Bcl-2, and Bcl-w) are often dysregulated in PC, increasing cell proliferation and drug resistance. Recent literature suggests the therapeutic advantage of targeting both Mcl-1 and Bcl-xL in pancreatic cancer. Mcl-1 is reported to be a downstream target of CDK9, and I hypothesize that targeting CDK9 will sensitize pancreatic cancer cells to the Bcl-2 family inhibitor Navitoclax. In this study, I aim to treat pancreatic cancer cells with CDK9-specific proteolysis targeting chimera (PROTAC 2) and determine whether this treatment can sensitize the cancer cells to Bcl-2 family members specific inhibitor Navitoclax (ABT-263) and induce a robust cell growth inhibition. For this, I treated pancreatic cancer cells (T3M4) with PROTAC 2 and Navitoclax at varying concentrations (0.01 micromolar to 20 micromolar) for 72 h. Treatments of cancer cells with PROTAC 2 (5 micromolar) alone cause 21% cell growth inhibition, and Navitoclax alone (5 micromolar) causes 74% cell growth inhibition. Interestingly, a combination of PROTAC 2 and Navitoclax treatment causes 80% of cancer cell growth inhibition (p<0.0005). These results suggest CDK9-specific PROTAC 2 treatment sensitizes pancreatic cancer cells to the Bcl-2 inhibitor Navitoclax. The combination of PROTAC 2 and Navitoclax can be utilized as a potent targeted therapy against highly lethal pancreatic cancer.

Competition history

  • AJAS 2025 Category not listed

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Source: AAAS Annual Meeting (Confex) / American Junior Academy of Science

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