Abstract
Simple SummaryCyclin-dependent kinase (CDK) 4/6 inhibitors, in combination with endocrine therapies, are now the standard of care for patients with metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. Despite the effectiveness of CDK4/6 inhibitors, acquired resistance occurs in almost all cases. We developed and used a palbociclib-resistant preclinical model and studied the overcoming strategies, using FDA-approved chemotherapy in combination with a CDK4/6 inhibitor. We demonstrated that sequential abemaciclib treatment following eribulin-enhanced anti-tumor activity in vitro and in vivo on the CDK4/6 inhibitor-resistant cells by more effectively inhibiting the G2/M cell cycle phase. The sequential combination of abemaciclib following eribulin could be an effective treatment strategy in overcoming resistance to CDK4/6 inhibitors in HR-positive breast cancer.Breast cancer remains a leading cancer burden among women worldwide. Acquired resistance of cyclin-dependent kinase (CDK) 4/6 inhibitors occurs in almost all hormone receptor (HR)-positive subtype cases, comprising 70% of breast cancers, although CDK4/6 inhibitors combined with endocrine therapy are highly effective. CDK4/6 inhibitors are not expected to cooperate with cytotoxic chemotherapy based on the basic cytotoxic chemotherapy mode of action that inhibits rapidly proliferating cells. The palbociclib-resistant preclinical model developed in the current study investigated whether the combination of abemaciclib, CDK4/6 inhibitor with eribulin, an antimitotic chemotherapy could be a strategy to overcome palbociclib-resistant HR-positive breast cancer. The current study demonstrated that sequential abemaciclib treatment following eribulin synergistically suppressed CDK4/6 inhibitor-resistant cells by inhibiting the G2/M cell cycle phase more effectively. The current study showed the significant association of the pole-like kinase 1 (PLK1) level and palbociclib resistance. Moreover, the cumulative PLK1 inhibition in the G2/M phase by each eribulin or abemaciclib proved to be a mechanism of the synergistic effect. The synergistic antitumor effect was also supported by in vivo study. The sequential combination of abemaciclib following eribulin merits further clinical trials to overcome resistance to CDK4/6 inhibitors in HR-positive breast cancer.
Highlights
Breast cancer is the most common malignancy and a leading cause of cancer mortality among women globally [1]
The current study investigated the potential synergism of combined eribulin and cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor in a palbociclib-resistant breast cancer setting
CDK4/6 inhibitors were previously reported not to arrest palbociclibresistant cells at the G1/S phase compared with palbociclib-sensitive cells [9]
Summary
Breast cancer is the most common malignancy and a leading cause of cancer mortality among women globally [1]. Eribulin suppresses mitosis by directly binding to microtubule ends, inhibiting microtubule growth and tubulin aggregate formation [13] This leads to the effective, irreversible mitotic block at the G2/M cell cycle phase, resulting in apoptosis [14]. Combining eribulin with CDK4/6 inhibitor could be an effective treatment strategy in overcoming resistance to CDK4/6 inhibitors, to block the escaped cells that pass the G1/S cell cycle phase irrespective of the CDK4/6 inhibitor treatment. Based on these rationales, the current study investigated the potential synergism of combined eribulin and CDK4/6 inhibitor in a palbociclib-resistant breast cancer setting
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