Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7

Ingrid E. Wertz (), Saritha Kusam, Cynthia Lam, Toru Okamoto, Wendy Sandoval, Daniel J. Anderson, Elizabeth Helgason, James A. Ernst, Mike Eby, Jinfeng Liu, Lisa D. Belmont, Joshua S. Kaminker, Karen M. O’Rourke, Kanan Pujara, Pawan Bir Kohli, Adam R. Johnson, Mark L. Chiu, Jennie R. Lill, Peter K. Jackson, Wayne J. Fairbrother, Somasekar Seshagiri, Mary J. C. Ludlam, Kevin G. Leong, Erin C. Dueber, Heather Maecker, David C. S. Huang and Vishva M. Dixit
Additional contact information
Ingrid E. Wertz: Genentech
Saritha Kusam: Genentech
Cynthia Lam: Genentech
Toru Okamoto: The Walter and Eliza Hall Institute of Medical Research
Wendy Sandoval: Genentech
Daniel J. Anderson: Genentech
Elizabeth Helgason: Genentech
James A. Ernst: Genentech
Mike Eby: Genentech
Jinfeng Liu: Genentech
Lisa D. Belmont: Genentech
Joshua S. Kaminker: Genentech
Karen M. O’Rourke: Genentech
Kanan Pujara: Genentech
Pawan Bir Kohli: Genentech
Adam R. Johnson: Genentech
Mark L. Chiu: Abbott Laboratories
Jennie R. Lill: Genentech
Peter K. Jackson: Genentech
Wayne J. Fairbrother: Genentech
Somasekar Seshagiri: Genentech
Mary J. C. Ludlam: Genentech
Kevin G. Leong: Genentech
Erin C. Dueber: Genentech
Heather Maecker: Genentech
David C. S. Huang: The Walter and Eliza Hall Institute of Medical Research
Vishva M. Dixit: Genentech

Nature, 2011, vol. 471, issue 7336, 110-114

Abstract: Abstract Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics1. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas1. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms2. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear2. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.

Date: 2011
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DOI: 10.1038/nature09779

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