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Pharmacologic activation of PKM2 slows lung tumor xenograft growth

K Mark Parnell1, Jason M Foulks, Rebecca N Nix

  • 1Astex Pharmaceuticals, Inc., Salt Lake City, UT, USA.

Molecular Cancer Therapeutics
|May 31, 2013
PubMed

Insights

Small molecules that activate pyruvate kinase M2 (PKM2) inhibit lung cancer cell proliferation, especially when serine is absent. These PKM2 activators also reduced tumor growth in vivo, suggesting potential as cancer therapeutics.

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Inactivation of pyruvate kinase M2 (PKM2) is linked to increased cancer cell tumorigenicity.
  • Targeting the PKM2 pathway presents a potential strategy for inhibiting tumor growth.

Purpose of the Study:

  • To investigate the therapeutic potential of small-molecule PKM2 activators.
  • To determine if PKM2 activation can inhibit cancer cell proliferation and tumor growth.

Main Methods:

  • Generation and testing of novel small-molecule PKM2 activators.
  • Biochemical and cell-based assays to measure PKM2 activity and cancer cell proliferation.
  • In vitro studies using lung cancer cell lines under varying nutrient conditions (presence/absence of serine).
  • In vivo studies using aggressive lung adenocarcinoma xenografts in mice.

Main Results:

  • Developed compounds demonstrated low nanomolar activity in PKM2 assays.
  • PKM2 activators significantly inhibited proliferation of lung cancer cell lines specifically when serine was absent.
  • Tumor growth of aggressive lung adenocarcinoma xenografts was inhibited by PKM2 activators.
  • No significant effect on cancer cell growth was observed under normal in vitro conditions.

Conclusions:

  • Small-molecule activation of PKM2 effectively inhibits cancer cell growth in vitro and in vivo, particularly under specific nutrient-deprived conditions.
  • PKM2 activators represent a promising therapeutic strategy for augmenting existing cancer treatments.
  • Targeting the PKM2 pathway offers a novel approach for cancer therapy development.

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