Decreased ER dependency after acquired resistance to CDK4/6 inhibitors

Iida, Masafumi; Toyosawa, Daichi; Nakamura, Misato; Tsuboi, Kouki; Tokuda, Emi; Niwa, Toshifumi; Ishida, Toru; Hayashi, Shin Ichi

doi:10.1007/s12282-020-01090-3

Cited by 15 publications

(12 citation statements)

References 31 publications

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“…As expected, the anti-tumor activity of all chemotherapeutic agents did not change in the two breast cancer cells lines resistant to PAL or ABE compared with their respective parental cell lines (Table 2). Similar findings were recently reported, but only two chemotherapeutic agents were assessed [10].…”

Section: Discussionsupporting

confidence: 88%

“…Recent preclinical studies suggested that the acquisition of resistance to CDK4/6 inhibitors renders cells insensitive to estrogen because of reduced ER-ɑ expression [9,10]. To clarify this hypothesis, we investigated estrogen sensitivity in the CDK4/6 inhibitor-sensitive or -resistant breast cancer cells in this study.…”

Section: Discussionmentioning

confidence: 98%

“…Based on the IC 50 s of PAL or ABE, the PAL-or ABE-resistant MCF-7 or KPL-1 cells were 3 to 6 times more cross-resistant to APL and ABE, respectively (Table 1). Cross-resistance among CDK4/6 inhibitors has been reported in both preclinical and clinical conditions [1,[10][11][12].…”

Section: Discussionmentioning

confidence: 99%

“…Resistance to CDK4/6 inhibitors was suggested to affect estrogen sensitivity [9,10]; therefore, the growth-promoting effects of E2 on the resistant and sensitive cells were investigated. These effects were significantly down-regulated in MR-P, MR-A, KR-P and KR-A cells compared with in MS and K-P cells (Online Resource 3).…”

Section: Sensitivity To E2 and Er-α Expression In The Resistant And Smentioning

confidence: 99%

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Resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors confers cross-resistance to other CDK inhibitors but not to chemotherapeutic agents in breast cancer cells

et al. 2020

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Background Combined endocrine therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor has been indicated to improve not only progression-free survival, but also overall survival in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. However, resistance to this combination therapy inevitably develops. How to manage this resistant breast cancer is one of the most important clinical issues. To investigate the mechanisms of action responsible for resistance, we developed breast cancer cells resistant to CDK4/6 inhibitors, and analyzed their biological characteristics and sensitivity to different anticancer agents. Methods HR-positive, HER2-negative MCF-7 and KPL-1 breast cancer cells were cultivated in palbociclib (PAL) or abemaciclib (ABE)-added culture medium for over 5 months, and we successfully developed PAL-or ABE-resistant cells. The effects of PAL or ABE on the cell growth, basal RB expression, RB phosphorylation, cell cycle and cell senescence were compared between resistant and parental cells. Effects of the other CDK4/6 inhibitor, different chemotherapeutic agents and estrogen on the cell growth were also examined. The expression levels of cyclin D1, CDK2, CDK4, CDK6, cyclin E1 and estrogen receptor (ER)-ɑ were measured using RT-PCR. Results Long-term exposure to up to 200 nM PAL or ABE resulted in the development of PAL-or ABE-resistant MCF-7 or KPL-1 breast cancer cells. Basal expression levels of RB in both resistant cells were down-regulated. Inhibitory effects of either PAL or ABE on RB phosphorylation were reduced in both resistant cells. Accordingly, G1-S cell cycle retardation and cell senescence induced by either inhibitor were also attenuated in both resistant cells. Both resistant cells were crossresistant to the other CDK4/6 inhibitor but almost as equally sensitive to different chemotherapeutic agents (5-fluorouracil, gemcitabine, paclitaxel, docetaxel, doxorubicin and eribulin) as the parental cells. The mRNA expression level of CDK6 significantly increased in the resistant MCF-7 cells and that of Rb1 significantly decreased in the resistant KPL-1 cells. Although both resistant cells were less sensitive to estrogen than the parental cells, the expression levels of ER-ɑ did not significantly change in either. Conclusions Our study suggests that acquired resistance to PAL or ABE confers cross-resistance to the other CDK4/6 inhibitor but not to chemotherapeutic agents in HR-positive, HER2-negative breast cancer cells. Down-regulation of basal RB expression and normalized RB phosphorylation reduced by CDK4/6 inhibitors may be responsible for the attenuated anti-cell growth effects of the inhibitors.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Sensitivity To E2 and Er-α Expression In The Resistant And Smentioning

confidence: 99%

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Resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors confers cross-resistance to other CDK inhibitors but not to chemotherapeutic agents in breast cancer cells

et al. 2020

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“…HPV positivity itself constitutes an intrinsic resistance mechanism to CDK4/6i's; acquired resistance may involve alterations in CDK2/6, Cyclin E, p21, p27, Rb, the PI3K-mTOR pathway, and the fibroblast growth factor receptor [139]. Additional acquired resistance mechanisms, mainly identified in BC, involve decreased dependence on estrogen receptor (ER) signaling (due to ER-alpha mutations), ER downregulation, IL6/STAT3 alteration, and DNA damage response pathways in vitro [137,140]. Notably, these resistance mechanisms were detected in clinical biopsies from BC patients progressing upon palbociclib [137].…”

Section: Resistance Mechanisms and Novel Combination Approachesmentioning

confidence: 99%

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

Riess

Irmscher

Salewski

et al. 2020

Cancer Metastasis Rev

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Cyclin-dependent kinases (CDK) control the cell cycle and play a crucial role in oncogenesis. Pharmacologic inhibition of CDK has contributed to the recent clinical approval of dual CDK4/6 inhibitors for the treatment of breast and small cell lung cancer. While the anticancer cell effects of CDK inhibitors are well-established, preclinical and early clinical studies describe additional mechanisms of action such as chemo- and radiosensitization or immune stimulation. The latter offers great potential to incorporate CDK inhibitors in immune-based treatments. However, dosing schedules and accurate timing of each combination partner need to be respected to prevent immune escape and resistance. In this review, we provide a detailed summary of CDK inhibitors in the two solid cancer types head and neck cancer and glioblastoma multiforme; it describes the molecular mechanisms of response vs. resistance and covers strategies to avoid resistance by the combination of immunotherapy or targeted therapy.

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