Targeting the Id1-Kif11-Aurka axis in triple negative breast cancer using combination therapy

Murali, R.; Varghese, B. A.; Karthikeyan, N.; T, A. P.; Teo, W. S.; McFarland, A.; Roden, D. L.; Holliday, H.; Konrad, C.; Cazet, A. S.; Dodson, E.; George, J. T.; Levine, H.; Jolly, M. K.; Swarbrick, A.; Nair, R.

doi:10.1101/760686

bioRxiv · 10.1101/760686

Targeting the Id1-Kif11-Aurka axis in triple negative breast cancer using combination therapy

Murali, R.·Varghese, B. A.·Karthikeyan, N.·T, A. P.·Teo, W. S.·McFarland, A.·Roden, D. L.·Holliday, H.·Konrad, C.·Cazet, A. S.·Dodson, E.·George, J. T.·Levine, H.·Jolly, M. K.·Swarbrick, A.·Nair, R.

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Abstract

Evidence points to breast cancer following a hierarchical model, with Cancer Stem Cells (CSCs) driving critical phenotypes of the bulk tumor. Chemoresistant CSCs are not an abstract concept but have clinical consequences as they drive relapse and ultimately lead to mortality in patients, making it imperative to understand how these subpopulations of cells survive. Our previous work (1-2) has demonstrated that the bHLH transcription factor, Inhibitor of Differentiation 1 (Id1) and its closely related family member Id3, have an important role in maintaining the CSC phenotype in the Triple Negative breast cancer (TNBC) subtype. A genetic screen conducted to further elucidate the molecular mechanism underlying the Id (Id1/3) mediated CSC phenotypes in TNBC revealed critical cell cycle genes such as Kif11 and Aurka as putative Id targets. We take this work forward by investigating how alteration in Kif11 and Aurka via Id proteins promotes the CSC phenotype in TNBC. Cells lacking Id are poised in a state of G0/G1 arrest from which they can re-enter the cell cycle. Intriguingly, depletion of Kif11 and Aurka independently did not phenocopy the G0/G1 arrest observed in Id knockdown (Id KD) cells. We have further explored the hypothesis that we can deplete the chemo resistant Id expressing CSC population by combining chemotherapy with targeted therapy using existing small molecule inhibitors (against Id target Kif11) to more effectively debulk the entire tumor. This work opens up exciting new possibilities of targeting Id targets like Kif11, in the TNBC subtype which is currently refractory to chemotherapy.

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Murali, R., Varghese, B. A., Karthikeyan, N., T, A. P., Teo, W. S., McFarland, A., Roden, D. L., Holliday, H., Konrad, C., Cazet, A. S., Dodson, E., George, J. T., Levine, H., Jolly, M. K., Swarbrick, A., Nair, R.. 2019-09-11. Targeting the Id1-Kif11-Aurka axis in triple negative breast cancer using combination therapy. https://doi.org/10.1101/760686

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