AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model
Cyclic GMP-AMP synthase (cGAS) is an endogenous DNA sensor that synthesizes cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) from ATP and GTP. 2′3′-cGAMP activates the stimulator of interferon genes (STING) pathway, resulting in the production of interferons and pro-inflammatory c...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/19/6721 |
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| author | Avijit Goswami Barnali Deb Sandeep Goyal Abhishek Gosavi Mukund Mali Ashwita M. Martis Princy Khurana Mukesh Gangar Digambar Raykar Ankita Mohanty Aditya Kulkarni |
| author_facet | Avijit Goswami Barnali Deb Sandeep Goyal Abhishek Gosavi Mukund Mali Ashwita M. Martis Princy Khurana Mukesh Gangar Digambar Raykar Ankita Mohanty Aditya Kulkarni |
| author_sort | Avijit Goswami |
| collection | DOAJ |
| description | Cyclic GMP-AMP synthase (cGAS) is an endogenous DNA sensor that synthesizes cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) from ATP and GTP. 2′3′-cGAMP activates the stimulator of interferon genes (STING) pathway, resulting in the production of interferons and pro-inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the phosphodiesterase that negatively regulates the STING pathway by hydrolyzing 2′3′-cGAMP. It has been established that the cGAS–STING pathway plays a major role in inhibiting tumor growth by upregulating T cell response. Herein, we demonstrate that AVA-NP-695, a selective and highly potent ENPP1 inhibitor, apart from the immunomodulatory effect also modulates cancer metastasis by negatively regulating epithelial–mesenchymal transition (EMT). We established that the combined addition of 2′3′-cGAMP and AVA-NP-695 significantly abrogated the transforming growth factor beta (TGF-ꞵ)-induced EMT in MDA-MB-231 cells. Finally, results from the in vivo study showed superior tumor growth inhibition and impact on tumor metastasis of AVA-NP-695 compared to Olaparib and PD-1 in a syngeneic 4T1 breast cancer mouse model. The translation of efficacy from in vitro to in vivo 4T1 tumor model provides a strong rationale for the therapeutic potential of AVA-NP-695 against triple-negative breast cancer (TNBC) as an immunomodulatory and anti-metastatic agent. |
| first_indexed | 2024-03-09T21:23:14Z |
| format | Article |
| id | doaj.art-f597e29de0c943f99dc61d9a681ec00a |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T21:23:14Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f597e29de0c943f99dc61d9a681ec00a2023-11-23T21:16:08ZengMDPI AGMolecules1420-30492022-10-012719672110.3390/molecules27196721AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse ModelAvijit Goswami0Barnali Deb1Sandeep Goyal2Abhishek Gosavi3Mukund Mali4Ashwita M. Martis5Princy Khurana6Mukesh Gangar7Digambar Raykar8Ankita Mohanty9Aditya Kulkarni10AtenPorus Lifesciences, Bangalore 560068, IndiaAtenPorus Lifesciences, Bangalore 560068, IndiaAtenPorus Lifesciences, Bangalore 560068, IndiaAtenPorus Lifesciences, Bangalore 560068, IndiaAtenPorus Lifesciences, Bangalore 560068, IndiaAtenPorus Lifesciences, Bangalore 560068, IndiaAtenPorus Lifesciences, Bangalore 560068, IndiaAtenPorus Lifesciences, Bangalore 560068, IndiaAtenPorus Lifesciences, Bangalore 560068, IndiaAtenPorus Lifesciences, Bangalore 560068, IndiaAtenPorus Lifesciences, Bangalore 560068, IndiaCyclic GMP-AMP synthase (cGAS) is an endogenous DNA sensor that synthesizes cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) from ATP and GTP. 2′3′-cGAMP activates the stimulator of interferon genes (STING) pathway, resulting in the production of interferons and pro-inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the phosphodiesterase that negatively regulates the STING pathway by hydrolyzing 2′3′-cGAMP. It has been established that the cGAS–STING pathway plays a major role in inhibiting tumor growth by upregulating T cell response. Herein, we demonstrate that AVA-NP-695, a selective and highly potent ENPP1 inhibitor, apart from the immunomodulatory effect also modulates cancer metastasis by negatively regulating epithelial–mesenchymal transition (EMT). We established that the combined addition of 2′3′-cGAMP and AVA-NP-695 significantly abrogated the transforming growth factor beta (TGF-ꞵ)-induced EMT in MDA-MB-231 cells. Finally, results from the in vivo study showed superior tumor growth inhibition and impact on tumor metastasis of AVA-NP-695 compared to Olaparib and PD-1 in a syngeneic 4T1 breast cancer mouse model. The translation of efficacy from in vitro to in vivo 4T1 tumor model provides a strong rationale for the therapeutic potential of AVA-NP-695 against triple-negative breast cancer (TNBC) as an immunomodulatory and anti-metastatic agent.https://www.mdpi.com/1420-3049/27/19/6721cancer immunotherapyENPP1 inhibitorSTING2′3′-cGAMPEMT4T1 syngeneic model |
| spellingShingle | Avijit Goswami Barnali Deb Sandeep Goyal Abhishek Gosavi Mukund Mali Ashwita M. Martis Princy Khurana Mukesh Gangar Digambar Raykar Ankita Mohanty Aditya Kulkarni AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model Molecules cancer immunotherapy ENPP1 inhibitor STING 2′3′-cGAMP EMT 4T1 syngeneic model |
| title | AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model |
| title_full | AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model |
| title_fullStr | AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model |
| title_full_unstemmed | AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model |
| title_short | AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model |
| title_sort | ava np 695 selectively inhibits enpp1 to activate sting pathway and abrogate tumor metastasis in 4t1 breast cancer syngeneic mouse model |
| topic | cancer immunotherapy ENPP1 inhibitor STING 2′3′-cGAMP EMT 4T1 syngeneic model |
| url | https://www.mdpi.com/1420-3049/27/19/6721 |
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