Targeting CCR2+ macrophages with BET inhibitor overcomes adaptive resistance to anti-VEGF therapy in ovarian cancer

Wu, Yangjun; Jennings, Nicholas B.; Sun, Yunjie; Bayraktar, Emine; Corvigno, Sara; Stur, Elaine; Glassman, Deanna; Mangala, Lingegowda S.; Ahumada, Adrian Lankenau; Westin, Shannon N.; Sood, Anil K.; Hu, Wei

doi:10.1007/s00432-021-03885-z

Cited by 7 publications

(2 citation statements)

References 44 publications

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“…(S)-HDAC-42 and SB939 are both HDAC inhibitors and are part of a drug class that is widely studied in ovarian cancer 24 . CPI-203 is an epigenetic reader domain inhibitor that binds to the bromodomains of BRD4 and has previously been studied in the context of ovarian cancer 25 . In contrast, lestaurtinib (CEP-701, Teva), a broad spectrum tyrosine kinase inhibitor known to target FLT3, JAK2, and PRK1 26 , has never been studied in the context of ovarian cancer, thus we elected to further study this compound.…”

Section: Resultsmentioning

confidence: 99%

Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit advanced forms of therapy resistant ovarian cancer

Rodman,

Emch,

Hou

et al. 2024

Preprint

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Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited JNK and ERK activity, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer.Statement of significanceLestaurtinib is a novel inhibitor of ovarian cancer, including chemotherapy- and PARPi-resistant models, that acts through robust inhibition of the JAK/STAT pathway and synergizes with standard-of-care agents at clinically relevant concentrations.

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Section: Resultsmentioning

confidence: 99%

Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit advanced forms of therapy resistant ovarian cancer

Rodman,

Emch,

Hou

et al. 2024

Preprint

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“…This compound could also enhance the efficacy of AVA therapy in ovarian cancer by inducing apoptosis in M2-like macrophages and reprogramming them to have an M1-like phenotype. BETi has been shown to overcome resistance to AVA treatment and increase survival in an adaptive resistance model of ovarian cancer (Figure 3) [193].…”

Section: Tams In Conventional Cancer Therapiesmentioning

confidence: 99%

Macrophage-Based Therapeutic Strategies in Hematologic Malignancies

Khalili,

Zeinali,

Moghadam Fard

et al. 2023

Cancers

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Macrophages are types of immune cells, with ambivalent functions in tumor growth, which depend on the specific environment in which they reside. Tumor-associated macrophages (TAMs) are a diverse population of immunosuppressive myeloid cells that play significant roles in several malignancies. TAM infiltration in malignancies has been linked to a poor prognosis and limited response to treatments, including those using checkpoint inhibitors. Understanding the precise mechanisms through which macrophages contribute to tumor growth is an active area of research as targeting these cells may offer potential therapeutic approaches for cancer treatment. Numerous investigations have focused on anti-TAM-based methods that try to eliminate, rewire, or target the functional mediators released by these cells. Considering the importance of these strategies in the reversion of tumor resistance to conventional therapies and immune modulatory vaccination could be an appealing approach for the immunosuppressive targeting of myeloid cells in the tumor microenvironment (TME). The combination of reprogramming and TAM depletion is a special feature of this approach compared to other clinical strategies. Thus, the present review aims to comprehensively overview the pleiotropic activities of TAMs and their involvement in various stages of cancer development as a potent drug target, with a focus on hematologic tumors.

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