Overexpression of TK1 and CDK9 in plasma-derived exosomes is associated with clinical resistance to CDK4/6 inhibitors in metastatic breast cancer patients

Re, Marzia Del; Bertolini, Ilaria; Crucitta, Stefania; Fontanelli, Lorenzo; Rofi, Eleonora; Angelis, Claudia De; Diodati, Lucrezia; Cavallero, Diletta; Gianfilippo, Giulia; Salvadori, B.; Fogli, Stefano; Falcone, Alfredo; Scatena, Cristian; Naccarato, Antonio Giuseppe; Roncella, Manuela; Ghilli, Matteo; Morganti, Riccardo; Fontana, A.; Danesi, Romano

doi:10.1007/s10549-019-05365-y

Cited by 73 publications

(49 citation statements)

References 21 publications

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“…Also point mutations in ERBB2 have been associated with palbociclib and antiestrogen resistance; this resistance can, in vitro, be reverted by adding the HER2 kinase inhibitor neratinib [ 133 , 134 ]. The prospective, pharmacogenetic study ECLIPS is identifying predictive biomarkers in response to palbociclib plus ET combination treatment; results showed that the thymidine kinase-1 (TK1), key regulator of S/G2 phase, was significantly increased before treatment when compared after 3 months of treatment in patients who experienced disease progression, suggesting that TIK1 mRNA copies/mL can be correlated to acquired resistance to CDK4/6i [ 135 ]. Gene analysis results from 348 HR-positive HER2-negative metastatic BC samples showed that loss of FAT1, a tumor suppressor belonging to chaderin family involved in upregulation of CDK6 expression via Hippo pathway, is associated with a shorter PFS, suggesting its possible role as predictor of CDK4/6i resistance [ 136 ].…”

Section: Mechanisms Of Resistance and Potential Biomarkers Of Respmentioning

confidence: 99%

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Piezzo

Cocco

Caputo

et al. 2020

IJMS

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Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.

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Section: Mechanisms Of Resistance and Potential Biomarkers Of Respmentioning

confidence: 99%

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Piezzo

Cocco

Caputo

et al. 2020

IJMS

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“…Most primary breast tumors respond to initial treatments, but develop resistance months after initial response [ 129 , 130 ]. To overcome this resistance, exosomal miRNAs and exosomes transporting other molecular cargo have been explored as second-line treatments for refractory breast cancer in light of their essential role in tumor drug resistance ( Table 2 ) [ 131 ]. For example, exosome-mediated miR-567 was tested against HER2-enriched, trastuzumab-resistant breast cancer cell lines as a method to reverse autophagy-dependent chemoresistance [ 132 ].…”

Section: Exosomal Micrornas As Cancer Therapeuticsmentioning

confidence: 99%

Exosomal MicroRNAs and Organotropism in Breast Cancer Metastasis

Wong

Jalboush

2020

Cancers

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Breast cancer is the most frequent malignancy for women in which one in eight women will be diagnosed with the disease in their lifetime. Despite advances made in treating primary breast cancer, there is still no effective treatment for metastatic breast cancer. Consequently, metastatic breast cancer is responsible for 90% of breast cancer-related deaths while only accounting for approximately one third of all breast cancer cases. To help develop effective treatments for metastatic breast cancer, it is important to gain a deeper understanding of the mechanisms by which breast cancer metastasizes, particularly, those underlying organotropism towards brain, bone, and lungs. In this review, we will primarily focus on the roles that circulating exosomal microRNAs (miRNAs) play in organotropism of breast cancer metastasis. Exosomes are extracellular vesicles that play critical roles in intercellular communication. MicroRNAs can be encapsulated in exosomes; cargo-loaded exosomes can be secreted by tumor cells into the tumor microenvironment to facilitate tumor–stroma interactions or released to circulation to prime distant organs for subsequent metastasis. Here, we will summarize our current knowledge on the biogenesis of exosomes and miRNAs, mechanisms of cargo sorting into exosomes, the exosomal miRNAs implicated in breast cancer metastasis, and therapeutic exosomal miRNAs.

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“…Thymidine kinase 1 (TK1) plays a crucial role in DNA synthesis and cell proliferation [ 7 , 8 ]. In preliminary studies using the same assay, serum or plasma TK1 activity (sTKa, pTKa) was reported to be a prognostic circulating biomarker in early and advanced breast cancer [ 9 – 12 ]. The prognostic impact of baseline serum TK1 levels and TK1 variation in response to therapy was also reported in 159 samples from a phase III trial comparing AI and fulvestrant in ER+ HER2− MBC [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Plasma thymidine kinase 1 activity and outcome of ER+ HER2− metastatic breast cancer patients treated with palbociclib and endocrine therapy

et al. 2020

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Purpose Previous cohort studies have reported plasma TK1 activity (pTKa) as a potential prognostic biomarker in estrogen receptor-positive (ER+) HER2-negative (HER2−) metastatic breast cancer (MBC). In this prospective study, we report here the prognostic impact of pTKa in ER+/HER2− MBC patients treated with endocrine therapy and CDK4/6 inhibitor. Experimental design Patients were included into the prospective, ethics committee-approved ALCINA study (NCT02866149). Eligibility criteria were patients with ER+/HER2− MBC treated at Institut Curie with endocrine therapy and palbociclib. Plasma samples were obtained at baseline and after 4 weeks of treatment. pTKa was quantified by the DiviTum® assay (Biovica, Sweden). Results From May 2016 to August 2018, 103 patients treated with endocrine therapy and palbociclib were included. Patients had received a median of two prior systemic therapies for MBC (range 0–14). Median follow-up was 13.8 months (range 6–31), with median PFS and OS of 9.6 months (95%CI [7.0–11.3]) and 28 months (95%CI [23–not reached]), respectively. Median baseline pTKa was 292 Du/L (range 20–27,312 Du/L, IQR [89–853]). After adjusting for other prognostic factors, baseline pTKa remained an independent prognostic factor for both PFS (HR = 1.3 95%CI [1.1–1.4], p = 0.0005) and OS (HR = 1.3 95%CI [1.2–1.6], p < 0.0001), and 4-week pTKa was associated with OS (HR = 1.6 95%CI [1.3–2], p < 0.0001). That survival prediction was significantly improved by the addition of baseline pTKa to clinicopathological characteristics. Adding pTKa changes at 4 weeks to baseline pTKa did not further increase survival prediction. Conclusion This study demonstrates the clinical validity of pTKa as a new circulating prognostic marker in ER+/HER2− MBC patients treated with endocrine therapy and palbociclib.

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Overexpression of TK1 and CDK9 in plasma-derived exosomes is associated with clinical resistance to CDK4/6 inhibitors in metastatic breast cancer patients

Cited by 73 publications

References 21 publications

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Exosomal MicroRNAs and Organotropism in Breast Cancer Metastasis

Plasma thymidine kinase 1 activity and outcome of ER+ HER2− metastatic breast cancer patients treated with palbociclib and endocrine therapy

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