Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition

Gale, Molly; Li, Yao; Cao, Jian; Liu, Zongzhi Zachary; Holmbeck, Marissa A.; Zhang, Meiling; Lang, Sabine M.; Wu, Lizhen; Carmo, Mariana Do; Gupta, Swati; Aoshima, Keisuke; DiGiovanna, Michael P.; Stern, David F.; Rimm, David L.; Shadel, Gerald S.; Chen, Xiang; Yan, Qin

doi:10.1158/0008-5472.can-18-3985

Cited by 27 publications

(23 citation statements)

References 47 publications

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“…Our results indicated that FABP4 inhibited the expression of CPT-1 (Figure 6D). Oligomycin A, an ATP synthase inhibitor, 37 was found to dose-dependently inhibit ATP production in macrophages (Figure S8B). Further study showed that oligomycin A markedly inhibited the activity of NF-κB/RelA translocation and the downstream IL1α concentration, which were induced by knocking-down FABP4 (Figure 6E and F).…”

Section: Atpb Is Associated With Fabp4-regulated Nf-κb Activation In Macrophagesmentioning

confidence: 97%

FABP4 deactivates NF‐κB‐IL1α pathway by ubiquitinating ATPB in tumor‐associated macrophages and promotes neuroblastoma progression

Miao

Zhang

Tang

et al. 2021

Clinical & Translational Med

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Neuroblastoma (NB) is the most common and deadliest pediatric solid tumor. Targeting and reactivating tumor‐associated macrophages (TAMs) is necessary for reversing immune suppressive state and stimulating immune defense to exert tumoricidal function. However, studies on the function and regulation of TAMs in NB progression are still limited. Fatty acid binding protein 4 (FABP4) in TAMs was correlated with advanced clinical stages and unfavorable histology of NB. FABP4‐mediated macrophages increased migration, invasion, and tumor growth of NB cells. Mechanically, FABP4 could directly bind to ATPB to accelerate ATPB ubiquitination in macrophages. The consequently decreased ATP levels could deactivate NF‐κB/RelA‐IL1α pathway, which subsequently results in macrophages reprogrammed to an anti‐inflammatory phenotype. We also demonstrated that FABP4‐enhanced migration and invasion were significantly suppressed by IL1α blocking antibody. Furthermore, circulating FABP4 was also associated with the clinical stages of NB. Our findings suggest that FABP4‐mediated macrophages may promote proliferation and migration phenotypes in NB cells through deactivating NF‐κB‐IL1α pathway by ubiquitinating ATPB. This study reveals the pathologic and biologic role of FABP4‐mediated macrophages in NB development and exhibits a novel application of targeting FABP4 in macrophages for NB treatment.

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Section: Atpb Is Associated With Fabp4-regulated Nf-κb Activation In Macrophagesmentioning

confidence: 97%

FABP4 deactivates NF‐κB‐IL1α pathway by ubiquitinating ATPB in tumor‐associated macrophages and promotes neuroblastoma progression

Miao

Zhang

Tang

et al. 2021

Clinical & Translational Med

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“…Resistant cells were sensitive to inhibition of ATP synthase by oligomycin, and knockdown of F6 or β subunits rendered resistant cells responsive to a low dose of trastuzumab. Furthermore, combining ATP synthase inhibitor oligomycin with trastuzumab led to regression of trastuzumabresistant tumours in vivo (Gale et al 2020). A recent work on non-small-cell lung cancer cells subjected to X-ray irradiation showed that the expression level of the α subunit of ATP synthase is increased 24-96 h post-irradiation and that this is in line with an increased ATP hydrolysis in irradiated cells.…”

Section: Epigenetic Modulation Of Atp Synthase Induces Drug Resistancementioning

confidence: 96%

The role of mitochondrial ATP synthase in cancer

Galber

Acosta

Minervini

et al. 2020

Biological Chemistry

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The mitochondrial ATP synthase is a multi-subunit enzyme complex located in the inner mitochondrial membrane which is essential for oxidative phosphorylation under physiological conditions. In this review, we analyse the enzyme functions involved in cancer progression by dissecting specific conditions in which ATP synthase contributes to cancer development or metastasis. Moreover, we propose the role of ATP synthase in the formation of the permeability transition pore (PTP) as an additional mechanism which controls tumour cell death. We further describe transcriptional and translational modifications of the enzyme subunits and of the inhibitor protein IF1that may promote adaptations leading to cancer metabolism. Finally, we outline ATP synthase gene mutations and epigenetic modifications associated with cancer development or drug resistance, with the aim of highlighting this enzyme complex as a potential novel target for future anti-cancer therapy.

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“…In one recent study, the oxidative phosphorylation gene signature was found to be enriched in trastuzumab‐resistant cells, which were sensitive to inhibition of ATP synthase by oligomycin A and knockdown components of the ATP synthase complex; this resulted in the responsiveness of resistant cells to a low dose of trastuzumab. ATP synthase plays a pivotal role in the oxygen metabolic process, which may also be implicated in regulating CD44 high /CD24 low /EpCAM + BCSCs and thus regulating trastuzumab resistance in HER2‐positive breast cancer 89 . Cirenajwis et al revealed that PG11047 could lead to the decrease of approximately 50% of CD44 + /CD24 −/low BCSCs by targeting the polyamine metabolic pathway and inhibiting BCSC‐like properties, 90 but further studies are required to explore its function in vivo.…”

Section: Bcsc‐targeted Therapeutic Approaches For Overcoming Trastuzumab Resistancementioning

confidence: 99%

Cancer Stem Cell-Targeted Therapeutic Approaches for Overcoming Trastuzumab Resistance in HER2-Positive Breast Cancer

et al. 2021

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Application of the anti-HER2 drug trastuzumab has significantly improved the prognosis of patients with the HER2-positive subtype of breast cancer. However, 50% of patients with HER2 amplification relapse due to trastuzumab resistance. Accumulating evidence indicates that breast cancer is driven by a small subset of cancer-initiating cells or breast cancer stem cells (BCSCs), which have the capacity to self-renew and differentiate to regenerate the tumor cell hierarchy. Increasing data suggest that BCSCs are resistant to conventional therapy, including chemotherapy, radiotherapy, and endocrine therapy, which drives distant metastasis and breast cancer relapse. In recent years, the trastuzumab resistance of breast cancer has been closely related to the prevalence of BCSCs. Here, our primary focus is to discuss the role of epithelial-mesenchymal transition (EMT) of BCSCs in the setting of trastuzumab resistance and approaches of reducing or eradicating BCSCs in HER2-positive breast cancer.

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Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition

Cited by 27 publications

References 47 publications

FABP4 deactivates NF‐κB‐IL1α pathway by ubiquitinating ATPB in tumor‐associated macrophages and promotes neuroblastoma progression

FABP4 deactivates NF‐κB‐IL1α pathway by ubiquitinating ATPB in tumor‐associated macrophages and promotes neuroblastoma progression

The role of mitochondrial ATP synthase in cancer

Cancer Stem Cell-Targeted Therapeutic Approaches for Overcoming Trastuzumab Resistance in HER2-Positive Breast Cancer

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