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Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines

Cancer Chemotherapy and Pharmacology volume 69, pages 1601–1615 (2012)Cite this article

Abstract

Purpose

New targeted agents like antibodies or small molecules against tyrosine and lipid kinases clearly expand the standard therapy options in oncology. However, tumour resistance is still a challenge, often induced by mutations in growth-related signalling cascades. Twenty and ten percentage of all patients with colorectal and gastric cancers, respectively, carry phosphatidyl-3-kinase (PI3K) mutations and do not respond to receptor-blocking therapies. Recently, selective kinase inhibitors have been generated, which block the PI3K signalling pathway in tumour cells. So far, their therapeutic role for the treatment of mutated versus wild-type human gastrointestinal cancers has not been clarified in detail.

Methods

To define the inhibitory and pro-apoptotic effects of the two PI3K inhibitors BEZ235 and BKM120 in three human colon cancer (HT-29, HCT-116 and DLD-1) and three gastric cancer (NCI-n87, AGS and MKN-45), cell lines with different PIK3CA gene mutation status were used. Firstly, viability, apoptosis and caspase assays were performed during incubation with either the inhibitors alone or combined with different cytotoxic agents. Secondly, the molecular consequences for the cell cycle and signalling pathways were analysed by defining the protein levels by FACS and Western blot analysis.

Results

Both the PI3K inhibitors BEZ235 and BKM120 induced a clear concentration-dependent reduction in cell viability and an increase in apoptotic cell death, with the mutated cells being more sensitive to treatment. However, single-agent BEZ235 caused a G1 arrest in tumour cells, whilst BKM120 induced a G2 shift in a half of the gastrointestinal cancer cell lines. There was a clear downregulation in the protein levels of the PI3K–AKT pathway at the concentrations of 100nM for both agents and for BEZ235 the additional inhibition of the mTOR pathway. Furthermore, BEZ235 caused synergistic induction of apoptosis when combined with irinotecan in colon cancer cell lines. Human gastric cancer cells were less sensitive to both BEZ235 and BKM120.

Conclusions

BEZ235 and BKM120 induced pro-apoptotic effects in all cell lines and especially with an increased response in the PI3KCA mutated cells. Our data support the clinical development of these PI3K inhibitors for patients with wild-type or mutated colon cancers.

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Abbreviations

PI3K:

Phosphatidylinositol 3-kinase

EGFR:

Epidermal growth factor receptor

VEGF(R):

Vascular endothelial growth factor (receptor)

mTOR:

Mammalian target of rapamycin

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Acknowledgments

The authors thank Novartis, Basel, Switzerland, for supplying the PI3K inhibitors, and Julia Altmaier from the FACS Core Facility, Mainz, Germany, for assistance with the FACS analysis. We thank A. Warpakowski and A. Kinsella for drafting the manuscript of this study that was supported by Novartis, Basel. The authors also acknowledge the laboratory work of Erika Bachmann which was a part of her diploma thesis.

Conflict of interest

All authors declared no conflict of interest. There are no other financial or non-financial competing interests.

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  1. First Department of Internal Medicine, University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany

    Annett Mueller, Erika Bachmann, Monika Linnig, Katrin Khillimberger, Carl Christoph Schimanski, Peter R. Galle & Markus Moehler

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  1. Annett Mueller
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  2. Erika Bachmann
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Correspondence to Markus Moehler.

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Supplementary Figure 1. Apoptosis induction by combination of BEZ235 or BKM120 with chemotherapeutic agent 5-FU. Cells were treated with 1 and 2 μM of BEZ235 and BKM120 or either agent combined with 1 μg/mL 5-FU for 3 days, harvested, and the sub-G1 phase detected by flow cytometry. A, the combination of 5-FU with BEZ235 led to a synergistic induction of apoptosis only in HT-29 cells; no effect could be seen for the combination with BKM120. B, the treatment of 5-FU combined with BEZ235 or BKM120 did not intensify the induction of apoptosis in all gastric cancer cells. Results are displayed as mean with standard deviation of three independent experiments. Statistically significant (p<0.05) induction of apoptosis is displayed with p=; in such cases, the sum of the mono applications (substance and irinotecan) are significantly lower than the achieved synergistic effect (p<0.05). (PDF 47 kb)

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Mueller, A., Bachmann, E., Linnig, M. et al. Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines. Cancer Chemother Pharmacol 69, 1601–1615 (2012). https://doi.org/10.1007/s00280-012-1869-z

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Keywords

  • Inhibition
  • PI3K
  • Cancer cell lines
  • Chemotherapy
  • Wild type