Activating KRAS mutations, altered metabolism, and an immunosuppressive tumor microenvironment are all hallmarks of pancreatic ductal adenocarcinoma (PDAC). The recent groundbreaking discovery of KRASG12C specific inhibitors has reinvigorated hope for direct targeting of this dominant driver oncogene formerly deemed ?undruggable?. However, it is becoming increasingly clear that the therapeutic potential of mutant KRAS inhibitors in PDAC and other malignancies will only be realized if they are administered as components of rationally designed combination therapies. To identify actionable immunomodulatory and metabolic events triggered by KRASG12C inhibition in PDAC, transcriptomic, proteomic, and metabolomic analyses were performed in human and murine models. KRASG12C inhibition in pancreatic cancer cells limited the expression of immunosuppressive chemokines, increased antigen presentation pathways, reduced nutrient (glucose and glutamine) consumption, and the production of immunosuppressive metabolites (lactate). These studies indicate that KRASG12C inhibitors exert immune-priming effects in PDAC and support combinations with immune checkpoint blockade (ICB) agents. However, these immune-priming effects were accompanied by alterations in nucleotide metabolism and by elevated extracellular adenosine levels. This finding has great potential significance since adenosine is known to curtail anti-tumor immunity by engaging adenosine A2a/A2b receptors (A2aR/A2bR) on a broad array of immune cell types. Remaining to be determined, if these observations are to be exploited for therapeutic purposes in KRASG12C PDAC, are (i) the mechanisms by which KRASG12C inhibition modulates nucleotide metabolism and adenosine levels in PDAC cells, (ii) the requisite components of ICB (anti-PD-1 and/or anti-CTLA-4) when co-targeting KRASG12C and A2aR/A2bR in animal models, and (iii) whether targeting adenosine signaling promotes synergy between KRASG12C inhibition and ICB in patients with KRASG12C PDAC. Studies proposed in Aim 1 will test the hypothesis that elevations in adenosine levels induced by KRASG12C inhibition reflect alterations in nucleotide metabolism, leading both to increased pancreatic tumor cell adenosine efflux and to decreased adenosine uptake.
Aim 2 entails mechanistically-based testing of combinations co-targeting KRASG12C, A2aR/A2bR and conventional immune checkpoints in new orthotopic, metastatic and genetic murine models of KRASG12C pancreatic cancer.
Aim 3 consists of a first-in-human investigator-initiated phase IA/IB clinical trial to test the tolerability and efficacy of our combinations as second-line therapies in patients with pancreatic cancer. Proposed studies will establish a new mechanistic framework of interrelationships between KRASG12C inhibition, nucleotide metabolism, adenosine signaling, and immunosuppression both in mouse models of PDAC and in patients. They will also provide the foundation for forward and reverse translation studies to improve immunotherapy responses in patients with KRASG12C PDAC and, potentially, in other KRASG12C malignancies.
Immunotherapy has revolutionized the way we treat a number of malignancies, but to date its impact in pancreatic cancer has been marginal. We know, for example, that conventional immune checkpoint inhibitors approved for use in melanoma, lung cancer, and other solid tumors show little or no benefit for the vast majority of pancreatic cancer patients, and that additional ?priming? of the immune system will be absolutely necessary to overcome the intrinsic resistance of pancreatic tumors to immunotherapy. To achieve this goal, we will study in preclinical models of pancreatic cancer and in a clinical trial a new immunotherapeutic strategy that combines drugs across several therapeutic classes shown by our data to be highly interdependent.
