Abstract B070: Adaptive KRAS-MAPK signaling mediates resistance to CD73 blockade in pancreatic ductal adenocarcinoma
Khadija Turabi, Shwetapadma Dash, Lincoln Strickland, Alyssa Waller, MacKenzie Demmel, Jennifer M. Bailey-LundbergAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to therapy due to oncogenic KRAS signaling and an immunosuppressive tumor microenvironment. We previously established that CD73 is induced early during pancreatic tumorigenesis, where extracellular adenosine promotes disease progression through ADORA2B-dependent remodeling of the tumor microenvironment, including macrophage polarization, impaired lymphocyte activation, T cell exclusion, and aSMA+ fibroblast reprogramming. Pharmacologic CD73 inhibition with Quemliclustat restores antitumor immunity and delays PDAC progression; however, residual lesions persist, suggesting adaptive resistance. We investigated whether adaptive KRAS-MAPK signaling sustains the CD73-adenosine immunosuppressive program during therapeutic response.
Methods:
Residual PanIN lesions following Quemliclustat treatment were analyzed by single-cell RNA sequencing to identify adaptive signaling pathways. Ingenuity pathway analysis identified enrichment of MAPK activation, which was validated by phospho-ERK1/2 immunostaining. LsL-Kras G12D ; LsL-Trp53 R172H/+; Pdx:Cre (KPC) syngeneic flank tumors were treated with vehicle, Quemliclustat, daraxonrasib, trametinib, daraxonrasib plus Quemliclustat, or trametinib plus Quemliclustat. Tumor growth, phospho-ERK1/2, CD39/CD73 expression, and stromal remodeling were evaluated following treatment.
Results:
Single-cell RNA sequencing of residual lesions following CD73 inhibition identified proliferative neoplastic cells as a predominant surviving population and revealed significant enrichment of KRAS-MAPK signaling, consistent with activation of an adaptive therapeutic reprogramming response. Increased phospho-ERK1/2 confirmed adaptive MAPK activation in resistant lesions (P<0.0001) and in established KPC tumors following Quemliclustat treatment (P<0.05), demonstrating induction of KRAS-MAPK signaling during CD73-targeted therapy. Pharmacologic MAPK inhibition with Trametinib reduced CD73 expression in vivo (P<0.0001), supporting MAPK signaling as an upstream regulator of the CD73-adenosine pathway. Combined Daraxonrasib and Quemliclustat treatment produced the greatest suppression of KPC tumor growth (P<0.0001), accompanied by significant reductions in CD73 expression (P<0.001) and reduced stromal aSMA compared with vehicle or either monotherapy. Although Trametinib reduced CD73 expression, Trametinib plus Quemliclustat did not further improve tumor growth suppression, indicating that direct KRAS inhibition more effectively suppresses adaptive therapeutic signaling than downstream MEK inhibition.
Conclusions:
Adaptive KRAS-MAPK signaling represents a previously unrecognized resistance mechanism that emerges following CD73 inhibition and sustains the CD73-adenosine immunosuppressive program in PDAC. Dual targeting of KRAS and CD73 suppresses adaptive signaling, reduces stromal remodeling, and produces superior antitumor activity, providing a mechanistically informed therapeutic strategy to overcome resistance to CD73-directed therapy in pancreatic cancer.
Citation Format:
Khadija Turabi, Shwetapadma Dash, Lincoln Strickland, Alyssa Waller, MacKenzie Demmel, Jennifer M. Bailey-Lundberg. Adaptive KRAS-MAPK signaling mediates resistance to CD73 blockade in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B070.