A Novel Sequential Treatment of Palbociclib Enhances the Effect of Cisplatin in RB-Proficient Triple-Negative Breast Cancer

Abstract

Background: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy lack of sensitivity to chemo-, endocrine and targeted therapy. CDK4/6 inhibitors, combined with endocrine therapy, have been proven to be effective in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. So we investigated that whether CDK4/6 inhibitor palbociclib (PD) could enhance effects of cisplatin (CDDP) on TNBC.Methods: The effects of different drug regimens of PD and CDDP on MDA-MB-231 and RB-knockdown MDA-MB-231 (sh-MDA-MB-231) cells was assessed in vitro and vivo. Immunoblotting illustrated cyclin D1/RB/E2F axis signaling pathway.Results: PD induced G1 phase cell cycle arrest in MDA-MB-231 cell line. However, neither concomitant treatment with PD and CDDP nor immediately sequential treatment with CDDP before or after PD had an influence on cell apoptosis of MDA-MB-231 cells. We further investigated the effect of PD or CDDP withdrawal on the sequential treatment and found that PD used for 48h and then withdrawn for 48h followed by CDDP could significantly increase apoptosis, inhibit cell proliferation, cloning formation and mitotic progression of MDA-MB-231 cells, while in other regimens PD and CDDP represented additive or antagonistic response. PD preferential use synchronized tumor cell cycle which could increase DNA damage by CDDP as measured by γH2AX. These findings above were negative in sh-MDA-MB-231 cells, which indicated that PD enhances the sensitivity of TNBC cells to CDDP in a RB dependent manner. In vivo, this combination treatment inhibited tumor growth and Ki-67 expression compared with single drug treatments in MDA-MB-231 xenograft models. Western blotting analysis presented that PD enhanced sensitivity to CDDP through CDK4/6-cyclin D-RB-E2F pathway. Conclusions: This study indicates that the anti-tumor effect of PD-CDDP functions through CDK4/6-cyclin D1-RB-E2F pathway and the synchronization of cell cycle. PD-CDDP Our study provides a novel and potentially effective treatment for TNBC patients.

CDK4/6 inhibitors: A potential therapeutic approach for triple negative breast cancer

“…Separately, a recent study investigated the effects of palbociclib treatment preceding cisplatin chemotherapy. 110 In the MDA‐MB‐231 and MDA‐MB‐468 cell lines, palbociclib alone resulted in cell cycle arrest as expected, but when cells were treated in combination with cisplatin, cell apoptosis was unaffected. This is due to the inability of the chemotherapeutic agent to act on already arrested cells.…”

“…Palbociclib alone did not affect tumor volume and weight, whereas cisplatin alone caused a significant decrease compared to vehicle control. 110 Further inhibition in tumor growth was observed in the sequential treatment group, with lower tumor Ki‐67 expression than that seen in single treatments and vehicle controls. Thus, pretreatment with palbociclib sensitizes cells to cisplatin and further increases its antitumor effect.…”

RB expression confers sensitivity to CDK4/6 inhibitor–mediated radiosensitization across breast cancer subtypes

“…Multiple preclinical studies support the hypothesis that CDK4/6 inhibition can improve the efficacy of standard chemotherapy treatments (such as paclitaxel and cisplatin) in TNBC and other cancer types by inducing apoptosis or potentiating DNA damage and causing increased cell death (11)(12)(13)(14)(15)(16). Previous studies combining low doses of CDK4/6 inhibition with RT demonstrate clinically-meaningful radiosensitization in ER+ breast cancer models (17), though others have since suggested that combination treatment may be most effective when RT is administered prior to CDK4/6 inhibitor therapy (18).…”

Proteomic characterisation of triple negative breast cancer cells following CDK4/6 inhibition

“…A common characteristic of Palbociclib treatment is the induction of a morphologically and phenotypically distinct cell state, which resembles senescence 13 , 14 , 17 , 18 , 23 . The senescent-like state can be induced in subtypes with functional Rb such as the Triple Negative Breast Cancer (TNBC) cell line, MDA-MB-231 13 , 15 , 17 , 23 – 26 . This cell state remains poorly understood as studies show inconclusive evidence creating uncertainty as to whether this is stable senescence 5 , 13 – 15 , 23 , 25 .…”