However, naked miRNA has a short half-life in plasma due to its vulnerability to ribonucleases, shows limited tumor penetration and cellular uptake due to its negative charge, and has off-target effects due to non-specific delivery ( 21). Inhibiting these tumorigenic effects of eEF2K via exogenous administration of miRNA-22 represents a potential therapeutic approach to improve the response of TNBC to chemotherapy and/or immunotherapy with immune checkpoint inhibitors. Importantly, eEF2K was also found to enhance the expression of PD-L1, and is thus implicated for its role in blocking tumor immunosurveillance ( 20). MiRNA-22 has been shown to be downregulated in TNBC, reducing inhibitory control over the eukaryotic elongation 2 factor kinase (eEF2K), a tumor growth-promoting and chemoresistance-inducing protein ( 12, 19).
Indeed, miRNA-22 has been extensively studied as a regulator of tumor suppressor genes like p53 ( 13) and as a repressor of the oncogene c-Myc ( 14) in many different cancers, including TNBC ( 12), hormone-dependent breast cancer ( 15), and colon cancer ( 16), and for its roles in metastasis suppression in breast cancer, ovarian cancer ( 17), and in the sensitization of esophageal carcinoma to γ-ray radiation ( 18). Amongst the multitude of miRNAs, miRNA-22 (a chain of non-coding RNA consisting of 22 nucleotides) has been found to play a critical role in cancer initiation and progression processes ( 11, 12). Despite recent advances in developing therapeutics for treating TNBC such as immune checkpoint inhibitor immuotherapy ( 5), chemotherapy remains the most common recommended systemic regimens for TNBC, even though rapid development of chemoresistance is common ( 6).Īn emerging body of evidence has supported key functional roles of microRNAs (miRNAs) in sustaining tumor proliferation, resisting growth inhibitors and cell death, inducing tumor invasion and metastasis, and promoting angiogenesis ( 7), suggesting that miRNAs may function as valuable oncologic therapy targets ( 8, 9, 10). PARP inhibitors, such as olaparib and talazoparib, have been approved for TNBC with germline BRCA1 or BRCA2 gene mutations, but these are only reported in 15.4% of cases ( 4). The severity of TNBC is further aggravated due to the lack of broadly-applicable targeted therapies, and by a high-rate of early metastases to the central nervous system and lungs ( 3). Mechanisms to overcome the aggressiveness, histopathological heterogeneity, and prevalence of TNBC in younger women represent major unmet needs in contemporary cancer medicine ( 2). Triple-negative breast cancer (TNBC) accounts for up to 10–12% of all breast cancer cases, and has a 5-year survival that is 8–16% lower than the hormone-receptor positive (HR+) disease subtype ( 1). The present study highlights the translational potential of miRNA-22 nanotherapy for TNBC in combination with standard-of-care drugs. More importantly, drug synergy was identified between miRNA-22 and standard-of-care drugs against TNBC, providing a basis for rational therapeutic combinations for improved response Conclusions Our analysis revealed the dose-response relationship, suggested optimal treatment frequency for miRNA-22 nanotherapy, and highlighted key determinants of therapy response, from which combination with immune checkpoint inhibitors was identified as a candidate strategy for improving treatment outcomes. To evaluate the translational potential of miRNA-22 nanotherapy, we developed a multiscale mechanistic model, calibrated to published in vivo data and extrapolated to the human scale, to describe and quantify the pharmacokinetics and pharmacodynamics of miRNA-22 in virtual patient populations. Moreover, exogenous administration of miRNA-22, loaded in nanoparticles to prevent degradation and improve tumor delivery (termed miRNA-22 nanotherapy), to suppress eEF2K production has shown potential as an investigational therapeutic agent in vivo. Downregulation of miRNA-22 in triple-negative breast cancer (TNBC) is associated with upregulation of eukaryotic elongation 2 factor kinase (eEF2K) protein, which regulates tumor growth, chemoresistance, and tumor immunosurveillance.