Therapeutic Assessment of Targeting ASNS Combined with <scp>l</scp>-Asparaginase Treatment in Solid Tumors and Investigation of Resistance Mechanisms

Apfel, Verena; Bégué, Damien; Cordó, Valentina; Holzer, Laura; Martinuzzi, Laetitia; Buhles, Alexandra; Kerr, Gráinne; Barbosa, Inês; Naumann, Ulrike; Piquet, Michelle; Ruddy, David A.; Weiss, Andreas; Ferretti, Stéphane; Almeida, Reinaldo; Bonenfant, Débora; Tordella, Luca; Galli, Giorgio

doi:10.1021/acsptsci.0c00196

Cited by 18 publications

(10 citation statements)

References 31 publications

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“…5d-f ). While some of downregulated genes have been previously described as targets for cancer therapy such as asparaginase ( Aspg ) 82 , semaphorins (Sema3c) 83 , Adenosin A1 receptor ( Adora 1) 84 , phosphoenolpyruvate ( Pck1 ) 85 , their association with immune responses are still largely unexplored. Taken together, these data imply novel functions of Adam2 in the reprogramming of the tumor cells and TME to augment the cytotoxicity of antigen-specific T-cells.…”

Section: Resultsmentioning

confidence: 99%

In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer

Dervovic

Chen

Malik

et al. 2022

Preprint

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How the genetic landscape of a tumor governs the tumor's response to immunotherapy remains largely elusive. Here, we established a direct in vivo CRISPR/Cas9 gene editing methodology to assess the immune-modulatory capabilities of 573 putative cancer genes associated with altered cytotoxic activity in human cancers. Using KrasG12D- and BrafV600E-driven mouse lung cancer models, we identify Serpinb9 and Adam2 as our top immune suppressive and immune enhancing genes, respectively. Mechanistically, we show that Serpinb9 ablation in KrasG12D- and BrafV600E-mutant lung tumor cells greatly enhances the efficacy of cytotoxic T-cells in vitro and in vivo. ADAM2 is a cancer testis antigen broadly expressed in human cancers such as lung adenocarcinoma (13.9%), renal (74.7%), prostate (72.4%), uterine (28.6%) and invasive breast (9.5%) cancer. In our mouse models, we show that Adam2 expression is induced in KrasG12D- but not BrafV600E-driven murine lung tumors and that its expression is further enhanced by immunotherapy. We show that loss of Adam2 significantly decreases KrasG12D-lung tumor burden but blocks the efficacy of cytotoxic T-cells. Consistently, Adam2 overexpression dramatically increases tumor growth and enhances immunotherapy efficacy. Mechanistically, we find that Adam2's oncogenic function depends on modulating the tumor immune microenvironment by restraining productive type I and type II interferon responses as well as cytokine signaling, reducing the presentation of tumor-associated antigen, and modulating surface expression of several immunoregulatory receptors within Kras-driven lung tumors. Adam2 expression also leads to reduced levels of immune checkpoint inhibitors such as Pd-l1, Lag3, Tigit and Tim3. This reduced exhaustion within the tumor microenvironment may explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy against Adam2 overexpressing lung tumors. Together, our study highlights the power of integrating cancer genomic with in vivo CRISPR/Cas9 screens to uncover how cancer-associated genetic alterations control responses to immunotherapies.

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Section: Resultsmentioning

confidence: 99%

In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer

Dervovic

Chen

Malik

et al. 2022

Preprint

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show abstract

“…TA inhibition of protein synthesis is of particular interest because Asparaginase, which depletes asparagine and glutamine, is in clinical use against leukemia (reviewed in Nikolaev 1969 ) and functions in part by suppressing protein synthesis ( Ellem et al, 1970 ; Kessel and Bosmann 1970 ; Benvenisty 1972 ) and by inhibiting mTORC1/S6K1 signaling ( Nikonorova et al, 2018 ). Asparaginase resistance remains a significant clinical problem ( Apfel et al, 2021 ) and as a protein drug, Asparaginase suffers from issues associated with instability and rapid clearance ( Varshosaz and Anvari 2018 ) and allergenicity ( Belen et al, 2019 ). Thus, a small molecule drug such as TA or a TA analog may be useful against Asparaginase-resistant malignancies or in patients with Asparaginase allergies.…”

Section: Discussionmentioning

confidence: 99%

Repurposing Tranexamic Acid as an Anticancer Agent

et al. 2022

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Tranexamic Acid (TA) is a clinically used antifibrinolytic agent that acts as a Lys mimetic to block binding of Plasminogen with Plasminogen activators, preventing conversion of Plasminogen to its proteolytically activated form, Plasmin. Previous studies suggested that TA may exhibit anticancer activity by blockade of extracellular Plasmin formation. Plasmin-mediated cleavage of the CDCP1 protein may increase its oncogenic functions through several downstream pathways. Results presented herein demonstrate that TA blocks Plasmin-mediated excision of the extracellular domain of the oncoprotein CDCP1. In vitro studies indicate that TA reduces the viability of a broad array of human and murine cancer cell lines, and breast tumor growth studies demonstrate that TA reduces cancer growth in vivo. Based on the ability of TA to mimic Lys and Arg, we hypothesized that TA may perturb multiple processes that involve Lys/Arg-rich protein sequences, and that TA may alter intracellular signaling pathways in addition to blocking extracellular Plasmin production. Indeed, TA-mediated suppression of tumor cell viability is associated with multiple biochemical actions, including inhibition of protein synthesis, reduced activating phosphorylation of STAT3 and S6K1, decreased expression of the MYC oncoprotein, and suppression of Lys acetylation. Further, TA inhibited uptake of Lys and Arg by cancer cells. These findings suggest that TA or TA analogs may serve as lead compounds and inspire the production of new classes of anticancer agents that function by mimicking Lys and Arg.

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“…TA inhibition of protein synthesis is of particular interest because Asparaginase, which depletes asparagine and glutamine, is in clinical use against leukemia (reviewed in (Nikolaev 1969)) and functions in part by suppressing protein synthesis (Benvenisty 1972, Ellem, et al 1970, Kessel and Bosmann 1970 and inhibiting mTORC1/S6K1 signaling (Nikonorova, et al 2018). Asparaginase resistance remains a significant clinical problem (Apfel, et al 2021) and as a protein drug, Asparaginase suffers from issues associated with instability and rapid clearance (Varshosaz and Anvari 2018) and allergenicity (Belen, et al 2019). Thus, a small molecule drug such as TA or a TA analog may be useful against Asparaginase-resistant malignancies or in patients with Asparaginase allergies.…”

Section: Discussionmentioning

confidence: 99%

Repurposing Tranexamic Acid as an Anticancer Agent

Law

Davis²,

Ghilardi³

et al. 2021

Preprint

View full text Add to dashboard Cite

Tranexamic Acid (TA) is a clinically used antifibrinolytic that acts as a lysine mimetic to block binding of Plasminogen with Plasminogen activators, preventing conversion of Plasminogen to its proteolytically activated form, Plasmin. Previous studies suggested that TA may exhibit anticancer activity by blockade of extracellular Plasmin formation. Plasmin-mediated cleavage of the CDCP1 protein may increase its oncogenic functions through several downstream pathways. Results presented herein demonstrate that TA blocks Plasmin-mediated excision of the extracellular domain of the oncoprotein CDCP1. In vitro studies indicate that TA reduces the viability of a broad array of human and murine cancer cell lines, and breast tumor growth studies demonstrate that TA reduces cancer growth in vivo. Based on the ability of TA to mimic lysine and arginine, we hypothesized that TA may perturb multiple processes that involve Lys/Arg-rich protein sequences, and that TA may alter intracellular signaling pathways in addition to blocking extracellular Plasmin production. Indeed, TA-mediated suppression of tumor cell viability is associated with multiple biochemical actions, including inhibition of protein synthesis, reduced activating phosphorylation of STAT3 and S6K1, decreased expression of the MYC oncoprotein, and suppression of Lys acetylation. These findings suggest that TA or TA analogs may serve as lead compounds and inspire the production of new classes of anticancer agents that function by mimicking Lys and Arg.

show abstract

Therapeutic Assessment of Targeting ASNS Combined with l-Asparaginase Treatment in Solid Tumors and Investigation of Resistance Mechanisms

Cited by 18 publications

References 31 publications

In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer

In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer

Repurposing Tranexamic Acid as an Anticancer Agent

Repurposing Tranexamic Acid as an Anticancer Agent

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