Related Experiment Video
Updated: Sep 11, 2025
Author Spotlight: Reprogramming Cancer Cells to iPSCs to Study Disease Progression and Treatment Targets
Published on: February 2, 2024
CDCP1-targeting ADC outperforms standard therapies in Ras-mutant pancreatic cancer
Yun Jung Um1, Hee-Dong Noh1, Jin Gu Cho2
1College of Pharmacy, Ajou University, 206 World Cup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do 16499, Republic of Korea.
Abstract:
R AS mutations are found in 10%-30% of various cancers and in up to 90% of pancreatic cancers, where they are associated with aggressive phenotypes, poor prognosis, and reduced overall survival. CUB domain containing protein 1 (CDCP1), a transcriptional target of activated RAS, is implicated in these cancers irrespective of the specific R AS mutation. Given the limited effectiveness of small-molecule inhibitors against mutant Ras-driven cancers, we developed a CDCP1-targeting antibody-drug conjugate (ADC). In this study, we demonstrate that CDCP1 overexpression significantly correlates with R AS mutations in pancreatic cancer. We generated and characterized a CDCP1-specific monoclonal antibody, 2G10, and conjugated it to the topoisomerase II inhibitor, PNU159682, to produce 2G10-PNU159682. The anti-tumor activity of this ADC was evaluated in vitro and in vivo using pancreatic cancer cell lines. 2G10-PNU159682 exhibited superior efficacy compared to MRTX1133 and sotorasib in G12D- and G12C-mutant cell lines. In a mouse xenograft model, 2G10-PNU159682 demonstrated robust anti-tumor activity against R AS-mutant pancreatic cancers, outperforming gemcitabine and FOLFIRINOX and achieving complete tumor remission for up to 100 days-even following relapse after standard chemotherapy. These findings support the potential of 2G10-PNU159682 as a promising therapeutic candidate for the treatment of Ras-mutant cancers.
Insights
A novel antibody-drug conjugate targeting CUB domain containing protein 1 (CDCP1) shows significant promise for treating Ras-mutant cancers, including pancreatic cancer. This new therapy, 2G10-PNU159682, demonstrated superior efficacy and long-lasting tumor remission in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Ras (R-RAS) mutations are prevalent in many cancers, particularly pancreatic cancer, correlating with aggressive disease and poor patient outcomes.
- CUB domain containing protein 1 (CDCP1) is a key target in Ras-driven cancers, regardless of specific R-RAS mutation.
- Existing small-molecule inhibitors show limited effectiveness against mutant Ras-driven cancers.
Purpose of the Study:
- To develop and evaluate a novel antibody-drug conjugate (ADC) targeting CDCP1 for the treatment of Ras-mutant cancers.
- To assess the correlation between CDCP1 overexpression and R-RAS mutations in pancreatic cancer.
- To investigate the anti-tumor activity of the CDCP1-targeting ADC, 2G10-PNU159682, in vitro and in vivo.
Main Methods:
- Generated and characterized a CDCP1-specific monoclonal antibody (2G10) and conjugated it to PNU159682, a topoisomerase II inhibitor.
- Evaluated the anti-tumor efficacy of 2G10-PNU159682 in pancreatic cancer cell lines with G12D and G12C R-RAS mutations.
- Assessed the in vivo anti-tumor activity in a mouse xenograft model of R-RAS-mutant pancreatic cancer.
Main Results:
- CDCP1 overexpression was found to significantly correlate with R-RAS mutations in pancreatic cancer.
- 2G10-PNU159682 demonstrated superior in vitro efficacy compared to MRTX1133 and sotorasib in G12D- and G12C-mutant cell lines.
- In vivo studies showed robust anti-tumor activity, achieving complete tumor remission for up to 100 days, outperforming gemcitabine and FOLFIRINOX.
Conclusions:
- The CDCP1-targeting ADC, 2G10-PNU159682, shows significant therapeutic potential for Ras-mutant cancers.
- This ADC offers a promising new treatment strategy, especially for pancreatic cancer, demonstrating durable responses even after chemotherapy relapse.
- Further clinical investigation of 2G10-PNU159682 is warranted for Ras-mutant cancer patients.
