Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer

Jennifer Y. Ge; Shaokun Shu; Mijung Kwon; Bojana Jovanović; Katherine Murphy; Anushree Gulvady; Anne Fassl; Anne Trinh; Yanan Kuang; Grace A. Heavey; Adrienne Luoma; Cloud Paweletz; Aaron R. Thorner; Kai W. Wucherpfennig; Jun Qi; Myles Brown; Piotr Sicinski; Thomas O. McDonald; David Pellman; Franziska Michor; Kornelia Polyak

doi:10.1038/s41467-020-16170-3

Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer

Jennifer Y. Ge, Shaokun Shu, Mijung Kwon, Bojana Jovanović, Katherine Murphy, Anushree Gulvady, Anne Fassl, Anne Trinh, Yanan Kuang, Grace A. Heavey, Adrienne Luoma, Cloud Paweletz, Aaron R. Thorner, Kai W. Wucherpfennig, Jun Qi, Myles Brown, Piotr Sicinski, Thomas O. McDonald, David Pellman, Franziska MichorKornelia Polyak

Department of Life Science

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

Abstract

BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.

Original language	English
Article number	2350
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16170-3
State	Published - 1 Dec 2020

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Publisher Copyright:
© 2020, The Author(s).

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Ge, J. Y., Shu, S., Kwon, M., Jovanović, B., Murphy, K., Gulvady, A., Fassl, A., Trinh, A., Kuang, Y., Heavey, G. A., Luoma, A., Paweletz, C., Thorner, A. R., Wucherpfennig, K. W., Qi, J., Brown, M., Sicinski, P., McDonald, T. O., Pellman, D., ... Polyak, K. (2020). Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer. Nature Communications, 11(1), Article 2350. https://doi.org/10.1038/s41467-020-16170-3

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title = "Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer",

abstract = "BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.",

author = "Ge, {Jennifer Y.} and Shaokun Shu and Mijung Kwon and Bojana Jovanovi{\'c} and Katherine Murphy and Anushree Gulvady and Anne Fassl and Anne Trinh and Yanan Kuang and Heavey, {Grace A.} and Adrienne Luoma and Cloud Paweletz and Thorner, {Aaron R.} and Wucherpfennig, {Kai W.} and Jun Qi and Myles Brown and Piotr Sicinski and McDonald, {Thomas O.} and David Pellman and Franziska Michor and Kornelia Polyak",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

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doi = "10.1038/s41467-020-16170-3",

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Ge, JY, Shu, S, Kwon, M, Jovanović, B, Murphy, K, Gulvady, A, Fassl, A, Trinh, A, Kuang, Y, Heavey, GA, Luoma, A, Paweletz, C, Thorner, AR, Wucherpfennig, KW, Qi, J, Brown, M, Sicinski, P, McDonald, TO, Pellman, D, Michor, F & Polyak, K 2020, 'Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer', Nature Communications, vol. 11, no. 1, 2350. https://doi.org/10.1038/s41467-020-16170-3

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AU - Ge, Jennifer Y.

AU - Shu, Shaokun

AU - Kwon, Mijung

AU - Jovanović, Bojana

AU - Murphy, Katherine

AU - Gulvady, Anushree

AU - Fassl, Anne

AU - Trinh, Anne

AU - Kuang, Yanan

AU - Heavey, Grace A.

AU - Luoma, Adrienne

AU - Paweletz, Cloud

AU - Thorner, Aaron R.

AU - Wucherpfennig, Kai W.

AU - Qi, Jun

AU - Brown, Myles

AU - Sicinski, Piotr

AU - McDonald, Thomas O.

AU - Pellman, David

AU - Michor, Franziska

AU - Polyak, Kornelia

PY - 2020/12/1

Y1 - 2020/12/1

N2 - BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.

AB - BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.

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SN - 2041-1723

VL - 11

JO - Nature Communications

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Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer

Abstract

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