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Targeting the Id1-Kif11 Axis in Triple-Negative Breast Cancer Using Combination Therapy

Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala 695014, India
Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India
The Kinghorn Cancer Centre and Cancer Research Theme, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW 2052, Australia
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA
Medical Science Training Program, Baylor College of Medicine, Houston, TX 77005, USA
Departments of Bioengineering and Physics, Northeastern University, Boston, MA 02115, USA
Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
Author to whom correspondence should be addressed.
Equal first authors.
Present address: Rajiv Gandhi Centre for Biotechnology, Kerala 695014, India.
Received: 25 June 2020 / Revised: 15 August 2020 / Accepted: 27 August 2020 / Published: 8 September 2020
(This article belongs to the Special Issue Biomolecules and Cancer Prevention)
The basic helix-loop-helix (bHLH) transcription factors inhibitor of differentiation 1 (Id1) and inhibitor of differentiation 3 (Id3) (referred to as Id) have an important role in maintaining the cancer stem cell (CSC) phenotype in the triple-negative breast cancer (TNBC) subtype. In this study, we aimed to understand the molecular mechanism underlying Id control of CSC phenotype and exploit it for therapeutic purposes. We used two different TNBC tumor models marked by either Id depletion or Id1 expression in order to identify Id targets using a combinatorial analysis of RNA sequencing and microarray data. Phenotypically, Id protein depletion leads to cell cycle arrest in the G0/G1 phase, which we demonstrate is reversible. In order to understand the molecular underpinning of Id proteins on the cell cycle phenotype, we carried out a large-scale small interfering RNA (siRNA) screen of 61 putative targets identified by using genomic analysis of two Id TNBC tumor models. Kinesin Family Member 11 (Kif11) and Aurora Kinase A (Aurka), which are critical cell cycle regulators, were further validated as Id targets. Interestingly, unlike in Id depletion conditions, Kif11 and Aurka knockdown leads to a G2/M arrest, suggesting a novel Id cell cycle mechanism, which we will explore in further studies. Therapeutic targeting of Kif11 to block the Id1–Kif11 axis was carried out using small molecular inhibitor ispinesib. We finally leveraged our findings to target the Id/Kif11 pathway using the small molecule inhibitor ispinesib in the Id+ CSC results combined with chemotherapy for better response in TNBC subtypes. This work opens up exciting new possibilities of targeting Id targets such as Kif11 in the TNBC subtype, which is currently refractory to chemotherapy. Targeting the Id1–Kif11 molecular pathway in the Id1+ CSCs in combination with chemotherapy and small molecular inhibitor results in more effective debulking of TNBC. View Full-Text
Keywords: cancer stem cells; chemoresistance; self-renewal; combination therapy; Id1; Kif11 cancer stem cells; chemoresistance; self-renewal; combination therapy; Id1; Kif11
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MDPI and ACS Style

Thankamony, A.P.; Murali, R.; Karthikeyan, N.; Varghese, B.A.; Teo, W.S.; McFarland, A.; Roden, D.L.; Holliday, H.; Konrad, C.V.; Cazet, A.; Dodson, E.; Yang, J.; Baker, L.A.; George, J.T.; Levine, H.; Jolly, M.K.; Swarbrick, A.; Nair, R. Targeting the Id1-Kif11 Axis in Triple-Negative Breast Cancer Using Combination Therapy. Biomolecules 2020, 10, 1295.

AMA Style

Thankamony AP, Murali R, Karthikeyan N, Varghese BA, Teo WS, McFarland A, Roden DL, Holliday H, Konrad CV, Cazet A, Dodson E, Yang J, Baker LA, George JT, Levine H, Jolly MK, Swarbrick A, Nair R. Targeting the Id1-Kif11 Axis in Triple-Negative Breast Cancer Using Combination Therapy. Biomolecules. 2020; 10(9):1295.

Chicago/Turabian Style

Thankamony, Archana P., Reshma Murali, Nitheesh Karthikeyan, Binitha A. Varghese, Wee S. Teo, Andrea McFarland, Daniel L. Roden, Holly Holliday, Christina V. Konrad, Aurelie Cazet, Eoin Dodson, Jessica Yang, Laura A. Baker, Jason T. George, Herbert Levine, Mohit K. Jolly, Alexander Swarbrick, and Radhika Nair. 2020. "Targeting the Id1-Kif11 Axis in Triple-Negative Breast Cancer Using Combination Therapy" Biomolecules 10, no. 9: 1295.

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