Combination of FTO and BTK inhibitors synergistically suppresses the malignancy of breast cancer cells

TL;DR

Combining FTO and BTK inhibitors strongly reduces breast cancer growth and spread in mice, suggesting a promising new treatment approach.

Contribution

This study identifies a synergistic drug combination of FTO and BTK inhibitors for breast cancer treatment.

Findings

Combining FTO and BTK inhibitors significantly suppresses breast cancer malignancy and lung metastasis in mice.

The drug combination reduces c-Myc and E2F1 expression by increasing mRNA m6A modification and decreasing stability.

Overexpression of c-Myc and E2F1 counteracts the antitumor effects of the drug combination.

Abstract

Despite significant progress in breast cancer treatment, more effective methods for its clinical management are still needed. Our data identified that fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) demethylase, is highly expressed in breast cancer and promotes tumorigenesis. Inhibiting FTO can suppress the proliferation and metastasis of breast cancer, while its efficacy needs to be further improved. Through screening with 27 clinically approved targeted therapy drugs, we discovered that ibrutinib, a BTK inhibitor, shows the highest cell death rate and lowest combination index (CI). This combination demonstrates a potent synergistic effect in the malignancy of breast cancer and its lung metastasis. RNA-seq showed that the oncogenic pathways regulated by c-Myc and E2F1 were among the most down-regulated in cells treated with FTO inhibitor and ibrutinib. Furthermore, this combination decreases the expression of both c-Myc and E2F1. Contrarily, overexpressing c-Myc and E2F1 counteracts this antitumor effectiveness. Mechanistically, this combination inhibits c-Myc and E2F1 expression by increasing m6A modification of their mRNAs and reducing their mRNA stability. In mouse models of cancer, combining FTO knockdown with ibrutinib markedly suppressed tumor growth, decreased metastasis, and improved survival. Collectively, the combined inhibition of FTO and BTK exhibited substantial synergistic anticancer effects in breast cancer. Our findings advocate for the evaluation of this combination in clinical trials.

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