Abstract 7310: PTPN1/2 inhibition with AC484 inhibits tumor metastasis
Authors: Yue Liu, Im-Meng Sun, Marc Creixell, Jordan S. Brown, Tuan Andrew Nguyen, Jiaxi Wang, Nianxin Yang, Ka Man Li, John Balibalos, Samir Kharbanda, Kayley Hake, Varahram Shahryari, Aaron W. Stebbins, Patrick M. Godfrey, Jonghyeob Lee, Chirag H. Patel, Po-Han Tai, Evangelia Malahias, Wenjun Kong, Kenneth J. Finn, Marcia N. Paddock, Fiona A. Harding, Jonathan D. Powell
Journal: Cancer Research (2025)

Abstract ABBV-CLS-484 (AC484) is a novel small molecule based immunotherapeutic drug that inhibits both PTPN2 and PTPN1 and is currently under clinical investigation for treating solid tumors. In preclinical syngeneic tumor models, AC484 has been shown to be efficacious as a monotherapy, in conjunction with checkpoint inhibitors (ICBs) in ICB-resistant tumors, as well as in adoptive cellular therapy (Baumgartner et al, Nature 2023). Given the potent efficacy of this immunomodulatory compound, we sought to investigate the potential role of PTPN1/2 inhibition as a means of preventing metastasis. To this end, we established spontaneous metastatic murine models of 4T1 breast cancer and CMT167 lung cancer. In both models, AC484 treatment was able to inhibit metastasis. Notably, AC484 reduced circulating tumor cells and suppressed tumor cell seeding and outgrowth in the lungs. Genetic deletion of PTPN1/2 in tumor cells failed to recapitulate this effect, indicating that PTPN1/2 inhibition was tumor cell extrinsic. Indeed, AC484 was ineffective in inhibiting metastasis in NSG mice, suggesting that it exerted its effects on immune cells. Antibody depletion experiments further demonstrated that both T cells and NK cells play critical roles in AC484-mediated anti-metastatic activity in the C57BL/6 CMT167 model, with NK cells appearing more dominant in the BALB/c 4T1 model. Careful kinetic analysis of these models demonstrated accumulation of myeloid cells, particularly neutrophils and monocyte-derived macrophages, both systemically and locally in the lungs. Importantly, this increase in myeloid population was observed prior to the formation of micro metastases and continued to escalate as lung metastasis advanced. These findings support a role for myeloid cells in altering the microenvironment to promote seeding, survival, and growth of metastatic tumor cells. Interestingly, while AC484 treatment prevented lung metastasis, it did not decrease myeloid cells. Rather, single-cell RNA sequencing of lung tissue from 4T1-bearing mice showed an increase in activation markers of myeloid cells, supporting a role for AC484 in modifying the metastatic microenvironment. Taken together, our data demonstrate the ability of PTPN1/2 inhibition to inhibit metastasis by enhancing anti-tumor immunity and altering the metastasis niche. These data provide the preclinical rationale for pursuing AC484 treatment in the neoadjuvant/adjuvant setting as a means of promoting the efficacy of cancer therapies with curative intent. Citation Format: Yue Liu, Im-Meng Sun, Marc Creixell, Jordan S. Brown, Tuan Andrew Nguyen, Jiaxi Wang, Nianxin Yang, Ka Man Li, John Balibalos, Samir Kharbanda, Kayley Hake, Varahram Shahryari, Aaron W. Stebbins, Patrick M. Godfrey, Jonghyeob Lee, Chirag H. Patel, Po-Han Tai, Evangelia Malahias, Wenjun Kong, Kenneth J. Finn, Marcia N. Paddock, Fiona A. Harding, Jonathan D. Powell. PTPN1/2 inhibition with AC484 inhibits tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7310.