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LRIG1 modulates cancer cell sensitivity to Smac mimetics by regulating TNFα expression and receptor tyrosine kinase

Longchuan Bai1, Donna McEachern, Chao-Yie Yang

  • 1University of Michigan Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.

Cancer Research
|January 14, 2012
PubMed

Insights

Smac mimetics trigger cancer cell death, but resistance is common. Downregulation of LRIG1 protein increases resistance by upregulating receptor tyrosine kinases (RTKs) and decreasing TNFα, suggesting combination therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Smac mimetics induce apoptosis in cancer cells by inhibiting apoptosis proteins.
  • Intrinsic and acquired resistance limit Smac mimetic efficacy.
  • LRIG1, a negative regulator of receptor tyrosine kinases (RTKs), plays a role in cancer cell signaling.

Purpose of the Study:

  • To elucidate mechanisms of intrinsic and acquired resistance to Smac mimetics.
  • To investigate the role of LRIG1 in Smac mimetic resistance.
  • To identify potential combination strategies to overcome Smac mimetic resistance.

Main Methods:

  • In vitro and in vivo studies using breast and ovarian cancer cell lines.
  • RNA interference to downregulate LRIG1 expression.
  • Treatment with Smac mimetic SM-164 and tyrosine kinase inhibitors (Crizotinib, GSK1363089).
  • Analysis of TNFα gene expression and RTK activity.

Main Results:

  • LRIG1 expression is downregulated in Smac mimetic-resistant cancer cells.
  • LRIG1 downregulation attenuates SM-164 efficacy, reduces TNFα induction, and increases RTK activity (c-Met, Ron).
  • Combination therapy with SM-164 and tyrosine kinase inhibitors (Crizotinib, GSK1363089) overcomes resistance and inhibits tumor growth in vivo.

Conclusions:

  • Downregulation of LRIG1 confers resistance to Smac mimetics through RTK upregulation and attenuated TNFα expression.
  • Targeting RTK signaling in combination with Smac mimetics offers a rational strategy to enhance anticancer efficacy and overcome resistance.

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