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Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer

Xiuning Le1,2,3, Rajee Antony1,2, Pedram Razavi4,5

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

Cancer Discovery
|September 9, 2016
PubMed

Insights

Proviral Insertion site in Murine leukemia virus (PIM) kinases cause resistance to PI3K inhibitors in breast cancer. Combining PIM and PI3K inhibition may overcome this resistance, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • PIK3CA mutations are common in breast cancer, driving oncogenesis.
  • PI3K inhibitors show promise but face resistance, limiting clinical efficacy.
  • Understanding resistance mechanisms is crucial for improving breast cancer treatment.

Purpose of the Study:

  • To identify genes conferring resistance to PI3K inhibitors.
  • To investigate the role of Proviral Insertion site in Murine leukemia virus (PIM) kinases in PI3K inhibitor resistance.
  • To evaluate combined PIM and PI3K inhibition as a therapeutic strategy.

Main Methods:

  • Systematic gain-of-function screening in breast cancer cells.
  • Pharmacologic inhibition of PI3K and PIM kinases.
  • Analysis of breast cancer biopsies for PIM expression and activity.

Main Results:

  • Upregulation of PIM kinases confers resistance to PI3K inhibitors by maintaining AKT-independent effector activation.
  • Combined PI3K and PIM inhibition overcomes this resistance.
  • Increased PIM expression/activity observed in resistant breast cancer biopsies.
  • PIM1 overexpression is mutually exclusive with PIK3CA mutation in treatment-naïve cancers.

Conclusions:

  • PIM kinases represent a novel mechanism of resistance to PI3K inhibitors.
  • Combined PIM/PI3K inhibition is a promising strategy for a subset of PIK3CA-mutant breast cancers.
  • Clinical studies of combined PIM/PI3K inhibition are warranted.

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