Abstract 6649: Inhibiting adenosine signaling and KRAS enhances the effect of α-PD-1 therapy in a KRASG12C/TP53R172H/+ pancreatic cancer model
Authors: LE THUC , Abt Evan , Kim Woosuk , Udyavar Akshata , Cho Arthur , Capri Joe , Cui Jing , Ghukasyan Razmik , Li Luyi , DiRenzo Daniel , Rosen Brandon , Donahue Timothy , Walters Matt , Radu Caius 
Published: September 2020

Introduction: High levels of adenosine (ADO) in the tumor microenvironment have been shown to suppress immune responses and curtail T cell activation in the presence of anti-PD-1/PD-L1 blocking antibodies. CD73 catalyzes the extracellular generation of ADO from adenosine monophosphate (AMP). KRAS mutations, of which 60% were derived from pancreatic ductal adenocarcinoma (PDAC) samples, were associated with significantly upregulated CD73 expression, which resulted in a worsening prognosis. These immunosuppressive effects can be counteracted by CD73 inhibitors or by a dual ADO receptor (A2aR/A2bR) antagonist.

Method: Linear models were used to evaluate the ability of 299 pan-cancer consensus oncogenic drivers to predict CD73 expression independent of tumor type in the TCGA dataset. Changes in gene expression induced by KRAS inhibition were determined by RNAseq. Metabolic and proteomic alterations induced by KRAS inhibition were determined by LC-MS. C57BL/6J mice bearing established KP4662-G12C (KRASG12C/TP53R172H/+) tumors (at least 150 mm3) were treated as indicated: A1421 (CD73i; 30 mg/kg/day, s.c.), anti-PD1 (Clone RMP 1-14; 10 mg/kg; twice per week, i.p), and MRTX-1257 (KRASi, 100 mg/kg/day, p.o.). Treatment efficacy was monitored in a blinded manner using micro-computed tomography (mCT). A1412 and MRTX-1257 were provided by Arcus Biosciences.

Data: Direct KRAS inhibition reduced but did not abolish CD73 and A2aR/A2bR expression in multiple PDAC models. Metabolic analyses indicated that KRAS inhibition increased ADO and AMP levels. KRAS inhibition in PDAC models induced gene expression changes consistent with increased tumor immunogenicity. In a murine model of pancreatic cancer-bearing the KRASG12C mutation, co-administration of a CD73 inhibitor with anti-PD-1 in established tumors resulted in significant tumor growth retardation, comparable to KRASG12C inhibition alone. Durable tumor regression was observed when mice were treated with the triple combination therapy. These data support the rationale for the clinical development of modulators of immunosuppressive adenosine signaling in pancreatic cancer.

Conclusion: Here, we show that direct inhibition of mutant KRAS in pancreatic cancer models yields complex immunomodulatory effects. While antigen presentation pathways are transcriptionally upregulated and the expression of immunosuppressive chemokine is reduced, KRAS inhibition also reprograms nucleotide metabolism leading to elevated levels of ADO. These findings suggest that co-targeting mutant KRAS and adenosine signaling may enhance immunotherapy against pancreatic cancer and potentially other KRAS driven malignancies.

Citation Format: THUC LE, Evan Abt, Woosuk Kim, Akshata Udyavar, Arthur Cho, Joe Capri, Jing Cui, Razmik Ghukasyan, Luyi Li, Daniel DiRenzo, Brandon Rosen, Timothy Donahue, Matt Walters, Caius Radu. Inhibiting adenosine signaling and KRAS enhances the effect of α-PD-1 therapy in a KRASG12C/TP53R172H/+ pancreatic cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6649.