Journal
CANCER RESEARCH
Volume 76, Issue 24, Pages 7168-7180Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-0155
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Funding
- Laura Ziskin Memorial Award (Entertainment Industry Foundation)
- NIH [R01 CA103866, AI47389]
- BCRF [01-06-00332]
- Komen Foundation [KG08169404, SAC110052]
- MDACC CCSG grant [P30 CA016672]
- [NIC-5K99CA180221]
- [0099031 U54CA112970]
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Aberrant activation of the PI3K/mTOR pathway is a common feature of many cancers and an attractive target for therapy, but resistance inevitably evolves as is the case for any cancer cell-targeted therapy. In animal tumor models, chronic inhibition of PI3K/mTOR initially inhibits tumor growth, but over time, tumor cells escape inhibition. In this study, we identified a context-dependent mechanism of escape whereby tumor cells upregulated the proto-oncogene transcriptional regulators c-MYC and YAP1. This mechanism was dependent on both constitutive ERK activity as well as inhibition of the stress kinase p38. Inhibition of p38 relieved proliferation arrest and allowed upregulation of MYC and YAP through stabilization of CREB. These data provide new insights into cellular signaling mechanisms that influence resistance to PI3K/mTOR inhibitors. Furthermore, they suggest that therapies that inactivate YAP or MYC or augment p38 activity could enhance the efficacy of PI3K/mTOR inhibitors.(C) 2016 AACR.
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