JAK2/STAT5 Inhibition Circumvents Resistance to PI3K/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer
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Britschgi, Adrian, Andraos-Rey, Rita, Brinkhaus, Heike, Klebba, Ina, Romanet, Vincent, Mueller, Urs, Murakami, Masato, Radimerski, Thomas and Bentires-Alj, Mohamed (2012) JAK2/STAT5 Inhibition Circumvents Resistance to PI3K/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer. Cancer Cell, 22 (6). pp. 796-811. ISSN 1535-6108
Abstract
Hyperactive PI3K/mTOR signaling is prevalent in the majority of human malignancies and its inhibition exhibits potent antitumor activity in a wide spectrum of solid cancers.
Unfortunately, single-agend targeted cancer therapy is usually thwarted by adaptive resistance.
Here, we report the discovery of a JAK2/STAT5-evoked positive feedback loop that causes resistance to dual PI3K/mTOR inhibition. Mechanistically, PI3K/mTOR inhibition increased IRS1-dependent activation of JAK2/STAT5 and secretion of IL-8 in several cell lines and primary triple-negative breast cancer. Genetic or pharmacological inhibition of JAK2 abrogated this feedback loop. We further show that combined PI3K/mTOR and JAK2 inhibition synergistically reduced cancer cell number in vitro, as well as tumor growth, the number of circulating tumor cells and metastasis in vivo.
This study reveals a new link between growth factor signaling, JAK/STAT activation and cytokine secretion.
Our results provide a rationale for combined targeting of the PI3K/mTOR and JAK2/STAT5 pathways in triple-negative breast cancer, a particularly aggressive and currently incurable disease.
| Item Type: | Article |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/6387 |