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Page 761 Remley et al. Cancer Drug Resist 2023;6:748-67 https://dx.doi.org/10.20517/cdr.2023.63

Another A2AR antagonist in development is AstraZeneca’s AZD4635. In a monotherapy phase 1 trial
(NCT02740985), observed adverse events included nausea, fatigue, and vomiting. In addition, one patient
with colorectal cancer had sudden death 15 days after the last dose of AZD4635, which was considered
treatment-related by the investigator. However, AZD4635 was well tolerated both as a monotherapy and in
combination with durvalumab in all patients. There were patients with responses such as stable disease,
partial response, and complete response and RNA analysis confirmed that in 5 of 7 patients, intertumoral
adenosine signaling decreased. Four of these 7 patients also had increases in gene-expression signatures of
cytolytic activity and IFN-γ signaling. These findings suggest that there were observable positive responses
to the treatment in some patients.

A2BR antagonists are also under investigation in several clinical trials. Arcus’ etrumadenant, a dual A2AR
and A2BR antagonist, is being evaluated in several cancers and was recently discontinued in mCRPC due to
a lack of efficacy (NCT05177770). Palofarma’s PBF-1129, an A2BR antagonist, is being evaluated in
metastatic NSCLC (NCT03274479) and EMD Serono’s M1069 (NCT05198349), another A2AR and A2BR
antagonist, is currently undergoing a first-in-human trial in patients with advanced malignancies. In
addition, Portage is evaluating TT-4, an A2BR antagonist, as a single agent in gastrointestinal cancer
(NCT04976660). Further investigation will likely provide more insights into the clinical potential of these
promising strategies. Overall, compounds exhibiting the highest water solubility tend to possess increased
bioavailability, making them more effective . With the advancement in the development of ADO receptor
[148]
antagonists, enhancing the solubility of these promising compounds while preserving their selectivity
emerges as an avenue for improvement.

CONCLUSION
In the complex battleground of cancer, it is necessary to understand the adaptations tumors employ to resist
therapies. This review has emphasized the role of ADO, a significant player in the TME, in driving
immunosuppression and fostering cancer drug resistance. The importance of ADO and its receptors,
particularly the A2AR and A2BR subtypes, in promoting an immune-escaping environment was thoroughly
explored.

Current research endeavors focus on various approaches to counteract immunosuppression, including
monoclonal antibodies against CD73 and the blockade of ADO receptors. Ongoing clinical trials investigate
combinations of these approaches with existing therapies, aiming to stimulate immune responses and
improve patient outcomes.

The results of ongoing clinical trials will inform new ways of overcoming cancer drug resistance. However,
further research is required to understand and fully exploit ADO’s pathway. Targeting ADO could improve
cancer treatments, providing hope for patients who previously had limited treatment options. This
underscores the importance of ongoing research in this area, aiming to improve the prognosis for all cancer
patients.

DECLARATIONS
Acknowledgments
The authors thank Schuyler Vinzant and Sara Adair for their critical feedback on the manuscript. All figures
were created using Biorender.