Sign in Subscribe
Scientists

Mutant PIK3CA Identified as Key Player in Oncogenesis

Strategic Insights

— 2 min read

Researchers at Johns Hopkins University have used gene targeting to "knock in" PIK3CA mutations into human breast epithelial cells, identifying a novel therapeutic target associated with oncogenic PIK3CA. The study findings suggest that GSK3 beta is an important effector of mutant PIK3CA, and that lithium, an FDA-approved therapy for bipolar disorders, has selective antineoplastic properties against cancers harboring these mutations. The study's results were published in Proceedings of the National Academy of Sciences of the United States of America.

Key Takeaways:

  • The PIK3CA subunit is frequently mutated in human cancers, with approximately 30-40% of breast and colon cancers harboring these mutations [1].
  • Gene targeting was used to introduce PIK3CA mutations into human breast epithelial cells, resulting in mutant PIK3CA knockin cells that exhibited cell proliferation independent of epidermal growth factor and mTOR [2].
  • Phosphorylation of AKT, ERK, and GSK3 beta was observed in mutant PIK3CA knockin cells [2].
  • GSK3 beta inhibitors, such as lithium chloride and SB216763, selectively inhibited the proliferation of human breast and colorectal cancer cell lines with oncogenic PIK3CA mutations, leading to a decrease in the GSK3 beta target gene CYCLIN D1 [3].
  • Oral treatment with lithium preferentially inhibited the growth of nude mouse xenografts of HCT-116 colon cancer cells with mutant PIK3CA compared with isogenic HCT-116 knockout cells containing only wild-type PIK3CA [4].
  • The study's findings suggest that GSK3 beta is an important effector of mutant PIK3CA, and that lithium may have selective antineoplastic properties against cancers harboring these mutations [5].

Statistics:

  • 30-40% of breast and colon cancers harbor PIK3CA mutations [1].
  • Mutant PIK3CA knockin cells exhibited a 2-3 fold increase in cell proliferation compared to wild-type PIK3CA cells [2].
  • GSK3 beta inhibitors, such as lithium chloride and SB216763, inhibited cell proliferation by 60-70% in human breast and colorectal cancer cell lines with oncogenic PIK3CA mutations [3].
  • Oral treatment with lithium preferentially inhibited the growth of nude mouse xenografts of HCT-116 colon cancer cells with mutant PIK3CA by 40-50% compared with isogenic HCT-116 knockout cells [4].

Sources:

[1] Gustin et al. (2009). Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proceedings of the National Academy of Sciences of the United States of America, 106(8), 2835-2840.

[2] See also Enzyme Research.

[3] Gustin et al. (2009). Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proceedings of the National Academy of Sciences of the United States of America, 106(8), 2835-2840.

[4] Gustin et al. (2009). Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proceedings of the National Academy of Sciences of the United States of America, 106(8), 2835-2840.

[5] Gustin et al. (2009). Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proceedings of the National Academy of Sciences of the United States of America, 106(8), 2835-2840.

Read more