Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo

Ramesh Elango,Sarah Ibrahim Binhamdan,Nehad M Alajez,Abdul-Aziz Siyal,Yasser A Alshawakir,Muthurangan Manikandan,Radhakrishnan Vishnubalaji,Abdullah Aldahmash,Musaad Alfayez

doi:10.1038/s41598-019-50140-0

Ramesh Elango, Sarah Ibrahim Binhamdan + Show 7 more

Open Access

https://doi.org/10.1038/s41598-019-50140-0

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Abstract

Despite recent advances in cancer management and therapy, resistance to cytotoxic medications remains a major clinical challenge; hence, combination-based anti-cancer treatment regimens are currently gaining momentum. PTC-209 reduced BMI1 protein expression, while palbociclib inhibited CDK4, Rb, and pRbSer795 protein expression in MDA-MB-231 cells. PTC-209 and palbociclib exhibited dose-dependent cytotoxic effects against MDA-MB-231 (breast), HCT116 (colon), and PC-3 (prostate) models, which was more profound in the combination group. Transcriptome and pathway analyses revealed inhibition of insulin signaling, focal adhesion, DNA damage response, and Wnt/pluripotency signaling pathways as well as cell proliferation, and cellular movement functional categories by PTC-209. Transcriptome and pathway analyses revealed palbociclib to mainly affect cell cycle progression and survival. Upstream analysis identified several networks affected by PTC-209 (EZH2, IFNB1, TRIB3, EGFR, SREBF1, IL1A, ERG, TGFB1, MAX, MNT) and palbociclib (RABL6, MITF, RARA, TAL1, AREG, E2F3, FOXM1, ESR1, ERBB2, and E2F). PTC-209 and palbociclib reduced colony and sphere formation, cell migration, and cell viability, which was further enhanced in the combination group. Concordantly, combination of PTC-209 and palbociclib exhibited more profound effects on MDA-MB-231 tumor formation in vivo. Our data suggest concurrent targeting of BMI1 and CDK4/CDK6 might provide novel therapeutic opportunity for breast, colon, and prostate cancer.

Highlights

Malignant transformation is a complex process manifested by the acquisition of sequential genetic alteration overtime[1,2]
Palbociclib is a highly selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK 4/6), which has been approved by the US Food and Drug Administration (FDA) to treat hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2−) breast cancer
We subsequently extended our investigations to the HCT116 and PC-3 cancer models, since those two models are known to harbor B Lymphoma Mo-MLV Insertion Region 1 Homolog (BMI1)+ cancer stem cells (CSCs) populations[37,38]

Summary

Introduction

Malignant transformation is a complex process manifested by the acquisition of sequential genetic alteration overtime[1,2]. Single cell analysis has revolutionized our understanding of tumorigeneses, revealing the complex nature of tumor mass, where different tumor cells within the tumor bulk appears to harbor distinct molecular signatures[3]. This phenomenon has a critical significance during tumor progression and the response to therapeutic interventions[4]. We provide the first experimental evidence on the therapeutic efficacy of combination of palbociclib and PTC-209 against a panel of cancer models (triple negative breast cancer (TNBC), colon, and prostate) and elucidated the molecular mechanisms by which concurrent targeting of TICs and cell cycle progression concurred tumor development

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