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PAK1 mediates resistance to PI3K inhibition in lymphomas.

Publication ,  Journal Article
Walsh, K; McKinney, MS; Love, C; Liu, Q; Fan, A; Patel, A; Smith, J; Beaven, A; Jima, DD; Dave, SS
Published in: Clin Cancer Res
March 1, 2013

PURPOSE: The phosphoinositide 3-kinase (PI3K) pathway is known to play an active role in many malignancies. The role of PI3K inhibition in the treatment of lymphomas has not been fully delineated. We sought to identify a role for therapeutic PI3K inhibition across a range of B-cell lymphomas. EXPERIMENTAL DESIGN: We selected three small molecule inhibitors to test in a panel of 60 cell lines that comprised diverse lymphoma types. We tested the selective PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitors BEZ235 and BGT226 in these cell lines. We applied gene expression profiling to better understand the molecular mechanisms associated with responsiveness to these drugs. RESULTS: We found that higher expression of the PAK1 gene was significantly associated with resistance to all three PI3K inhibitors. Through RNA-interference-mediated knockdown of the PAK1 gene, we showed a dramatic increase in the sensitivity to PI3K inhibition. We further tested a small-molecule inhibitor of PAK1 and found significant synergy between PI3K and PAK1 inhibition. CONCLUSION: Thus, we show that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

March 1, 2013

Volume

19

Issue

5

Start / End Page

1106 / 1115

Location

United States

Related Subject Headings

  • p21-Activated Kinases
  • Tumor Cells, Cultured
  • TOR Serine-Threonine Kinases
  • Small Molecule Libraries
  • Reverse Transcriptase Polymerase Chain Reaction
  • Real-Time Polymerase Chain Reaction
  • RNA, Small Interfering
  • RNA, Messenger
  • Quinolines
  • Phosphoinositide-3 Kinase Inhibitors
 

Citation

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Walsh, K., McKinney, M. S., Love, C., Liu, Q., Fan, A., Patel, A., … Dave, S. S. (2013). PAK1 mediates resistance to PI3K inhibition in lymphomas. Clin Cancer Res, 19(5), 1106–1115. https://doi.org/10.1158/1078-0432.CCR-12-1060
Walsh, Katherine, Matthew S. McKinney, Cassandra Love, Qingquan Liu, Alice Fan, Amee Patel, Jason Smith, Anne Beaven, Dereje D. Jima, and Sandeep S. Dave. “PAK1 mediates resistance to PI3K inhibition in lymphomas.Clin Cancer Res 19, no. 5 (March 1, 2013): 1106–15. https://doi.org/10.1158/1078-0432.CCR-12-1060.
Walsh K, McKinney MS, Love C, Liu Q, Fan A, Patel A, et al. PAK1 mediates resistance to PI3K inhibition in lymphomas. Clin Cancer Res. 2013 Mar 1;19(5):1106–15.
Walsh, Katherine, et al. “PAK1 mediates resistance to PI3K inhibition in lymphomas.Clin Cancer Res, vol. 19, no. 5, Mar. 2013, pp. 1106–15. Pubmed, doi:10.1158/1078-0432.CCR-12-1060.
Walsh K, McKinney MS, Love C, Liu Q, Fan A, Patel A, Smith J, Beaven A, Jima DD, Dave SS. PAK1 mediates resistance to PI3K inhibition in lymphomas. Clin Cancer Res. 2013 Mar 1;19(5):1106–1115.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

March 1, 2013

Volume

19

Issue

5

Start / End Page

1106 / 1115

Location

United States

Related Subject Headings

  • p21-Activated Kinases
  • Tumor Cells, Cultured
  • TOR Serine-Threonine Kinases
  • Small Molecule Libraries
  • Reverse Transcriptase Polymerase Chain Reaction
  • Real-Time Polymerase Chain Reaction
  • RNA, Small Interfering
  • RNA, Messenger
  • Quinolines
  • Phosphoinositide-3 Kinase Inhibitors