Main Session
Sep
28
PQA 03 - Digital Health Innovation and Informatics, Patient Safety & Quality, and Radiation and Cancer Biology
Presenter(s)
Sai Kumar Samala, MD, MBBS - University of California Los Angeles, Los Angeles, CA
S. K. Samala, P. C. Mallepaddi, P. M. Q. Mai, N. T. Tra, P. Biswal, B. M. Lakshmisha, G. Krouse, Y. Mackeyev, G. Vijay, and S. Krishnan; The University of Texas Health Science Center at Houston, Houston, TX
Purpose/Objective(s):
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a collagen-rich desmoplastic stroma and an immunosuppressive tumor immune microenvironment that limits therapeutic efficacy. Discoidin domain receptor 1 (DDR1), a collagen-activated receptor tyrosine kinase frequently overexpressed in PDAC, has been implicated in stromal signaling, survival pathways, and immune exclusion. We investigated whether pharmacologic DDR1 inhibition with 7rh, a small-molecule DDR1 inhibitor, enhances radiation therapy (RT) response and modulates immune-associated and stemness phenotypes in pancreatic cancer models.Materials/Methods:
DDR1 transcriptomic and proteomic expression were analyzed using cProSite datasets derived from TCGA and CPTAC. Immune correlation analyses were performed using publicly available datasets interrogated through TIMER3.0, TIDE, and UCSC Xena platforms. Murine (Panc02, KPC) and human (Panc1) pancreatic cancer cell lines were treated with RT ± 7rh. Clonogenic survival, MTS viability assays, and Annexin V/PI flow cytometry were used to assess treatment response. PD-L1, MHC-I, calreticulin, CD24, CD44, and E-cadherin expression were quantified by flow cytometry. Western blotting assessed DDR1 phosphorylation and downstream AKT signaling, and DNA damage response was evaluated by ?H2AX flow cytometry.Results:
DDR1 expression was elevated in PDAC compared with normal tissue and negatively correlated with CD8+ T-cell infiltration, immune score, and IFNG score, while positively correlating with MDSC infiltration and TIDE exclusion score. Treatment with 7rh plus RT significantly reduced viability compared with RT alone, with Bliss modeling supporting synergy. Clonogenic assays demonstrated radiosensitization (SER > 1.2) across all cell lines, consistent with impaired clonogenic survival following combination treatment. Western blotting showed dose-dependent suppression of pDDR1 and pAKT, and Annexin V/PI flow cytometry demonstrated increased apoptosis at 12–48 hours with combination therapy. ?H2AX analyses demonstrated persistent ?H2AX signal following combination treatment. Combination therapy increased PD-L1, MHC-I, and calreticulin expression, reduced CD24+/CD44+ stem-like populations, and increased E-cadherin expression.Conclusion:
DDR1 inhibition enhances radiation response in PDAC models and is associated with impaired clonogenic survival, persistent ?H2AX signal, immune-modulatory phenotypic changes, and decreased stem-like features. Integrative genomic analyses support DDR1 as a potential mediator of stromal-associated immune exclusion. These findings support further evaluation of DDR1 targeting as a radiosensitization strategy and as a partner for RT-based combination approaches, with ongoing studies investigating integration with immune checkpoint blockade in preclinical PDAC models.