Oncogenic KRAS-MAPK signaling sustains a CD73 dependent therapeutic vulnerability in pancreatic cancer
- 1University of Nebraska Medical Center
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is predominantly driven by oncogenic KRAS signaling and sustained by a desmoplastic, immunosuppressive microenvironment limiting therapeutic response. CD73 mediated adenosine signaling supports this immune-excluded, tumor supportive microenvironment. Whether dual targeting of KRAS-MAPK and CD73 signaling creates a therapeutic opportunity to improve tumor control remains unexplored. Analysis of KRAS mutant cancer cell lines revealed increased expression of NT5E and adenosine receptor ADORA2B. Pharmacologic and genetic suppression of oncogenic KRAS inhibited CD73 expression through a MAPK-dependent program. In syngeneic KPC tumors, conversely, CD73 inhibition with quemliclustat increased ERK phosphorylation in vivo, suggesting adaptive MAPK activation following CD73 blockade. Combined CD73 and RAS(ON) inhibition in vivo produced the strongest antitumor response, reducing endpoint tumor volume beyond either monotherapy. This combination significantly suppressed tumor proliferation and SMA-positive stroma and resulted in a substantial reduction in CD163-positive macrophage infiltration. RAS-MAPK targeted therapy was also associated with increased CD8-positive T cell infiltration and granzyme B-positive staining. As therapeutic responses in PDAC have been linked to the gut microbiome, we further examined treatment-associated changes in the microbiome. RAS-MAPK inhibition produced the most pronounced microbial alterations, which correlated with tumor volume and immune markers. Together, these findings identify KRAS-MAPK driven CD73 signaling as a therapeutic vulnerability in PDAC and support combined CD73 and RAS(ON) inhibition as a strategy to suppress tumor growth, remodel stroma, and alleviate tumor-associated immune suppression.
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BibTeX
@misc{turabi2026oncogenic,
title = {{Oncogenic KRAS-MAPK signaling sustains a CD73 dependent therapeutic vulnerability in pancreatic cancer}},
author = {K. Turabi and U. K. Sardarni and K. E. Ankenbauer and S. M. Torbit and V. Chandra and C. P. Taranto and S. Dash and A. Meade and A. T. Cephas and K. A. Klute and M. Pasca di Magliano and F. McAllister and T. McFall and K. E. DelGiorno and J. M. Bailey-Lundberg},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.20.760559},
url = {https://www.biorxiv.org/content/10.64898/2026.10.20.760559v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Oncogenic KRAS-MAPK signaling sustains a CD73 dependent therapeutic vulnerability in pancreatic cancer
AU - K. Turabi
AU - U. K. Sardarni
AU - K. E. Ankenbauer
AU - S. M. Torbit
AU - V. Chandra
AU - C. P. Taranto
AU - S. Dash
AU - A. Meade
AU - A. T. Cephas
AU - K. A. Klute
AU - M. Pasca di Magliano
AU - F. McAllister
AU - T. McFall
AU - K. E. DelGiorno
AU - J. M. Bailey-Lundberg
PY - 2026
DA - 2026/10/20
PB - bioRxiv
DO - 10.64898/2026.10.20.760559
UR - https://www.biorxiv.org/content/10.64898/2026.10.20.760559v1
AB - Pancreatic ductal adenocarcinoma (PDAC) is predominantly driven by oncogenic KRAS signaling and sustained by a desmoplastic, immunosuppressive microenvironment limiting therapeutic response. CD73 mediated adenosine signaling supports this immune-excluded, tumor supportive microenvironment. Whether dual targeting of KRAS-MAPK and CD73 signaling creates a therapeutic opportunity to improve tumor control remains unexplored. Analysis of KRAS mutant cancer cell lines revealed increased expression of NT5E and adenosine receptor ADORA2B. Pharmacologic and genetic suppression of oncogenic KRAS inhibited CD73 expression through a MAPK-dependent program. In syngeneic KPC tumors, conversely, CD73 inhibition with quemliclustat increased ERK phosphorylation in vivo, suggesting adaptive MAPK activation following CD73 blockade. Combined CD73 and RAS(ON) inhibition in vivo produced the strongest antitumor response, reducing endpoint tumor volume beyond either monotherapy. This combination significantly suppressed tumor proliferation and SMA-positive stroma and resulted in a substantial reduction in CD163-positive macrophage infiltration. RAS-MAPK targeted therapy was also associated with increased CD8-positive T cell infiltration and granzyme B-positive staining. As therapeutic responses in PDAC have been linked to the gut microbiome, we further examined treatment-associated changes in the microbiome. RAS-MAPK inhibition produced the most pronounced microbial alterations, which correlated with tumor volume and immune markers. Together, these findings identify KRAS-MAPK driven CD73 signaling as a therapeutic vulnerability in PDAC and support combined CD73 and RAS(ON) inhibition as a strategy to suppress tumor growth, remodel stroma, and alleviate tumor-associated immune suppression.
ER -