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Combined kinase inhibitors of MEK1/2 and either PI3K or PDGFR are efficacious in intracranial triple-negative breast cancer.

Publication ,  Journal Article
Van Swearingen, AED; Sambade, MJ; Siegel, MB; Sud, S; McNeill, RS; Bevill, SM; Chen, X; Bash, RE; Mounsey, L; Golitz, BT; Santos, C; Deal, A ...
Published in: Neuro-oncology
October 2017

Triple-negative breast cancer (TNBC), lacking expression of hormone and human epidermal growth factor receptor 2 receptors, is an aggressive subtype that frequently metastasizes to the brain and has no FDA-approved systemic therapies. Previous literature demonstrates mitogen-activated protein kinase kinase (MEK) pathway activation in TNBC brain metastases. Thus, we aimed to discover rational combinatorial therapies with MEK inhibition, hypothesizing that co-inhibition using clinically available brain-penetrant inhibitors would improve survival in preclinical models of TNBC brain metastases.Using human-derived TNBC cell lines, synthetic lethal small interfering RNA kinase screens were evaluated with brain-penetrant inhibitors against MEK1/2 (selumetinib, AZD6244) or phosphatidylinositol-3 kinase (PI3K; buparlisib, BKM120). Mice bearing intracranial TNBC tumors (SUM149, MDA-MB-231Br, MDA-MB-468, or MDA-MB-436) were treated with MEK, PI3K, or platelet derived growth factor receptor (PDGFR; pazopanib) inhibitors alone or in combination. Tumors were analyzed by western blot and multiplexed kinase inhibitor beads/mass spectrometry to assess treatment effects.Screens identified MEK+PI3K and MEK+PDGFR inhibitors as tractable, rational combinations. Dual treatment of selumetinib with buparlisib or pazopanib was synergistic in TNBC cells in vitro. Both combinations improved survival in intracranial SUM149 and MDA-MB-231Br, but not MDA-MB-468 or MDA-MB-436. Treatments decreased mitogen-activated protein kinase (MAPK) and PI3K (Akt) signaling in sensitive (SUM149 and 231Br) but not resistant models (MDA-MB-468). Exploratory analysis of kinome reprogramming in SUM149 intracranial tumors after MEK ± PI3K inhibition demonstrates extensive kinome changes with treatment, especially in MAPK pathway members.Results demonstrate that rational combinations of the clinically available inhibitors selumetinib with buparlisib or pazopanib may prove to be promising therapeutic strategies for the treatment of some TNBC brain metastases. Additionally, effective combination treatments cause widespread alterations in kinase pathways, including targetable potential resistance drivers.

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Published In

Neuro-oncology

DOI

EISSN

1523-5866

ISSN

1522-8517

Publication Date

October 2017

Volume

19

Issue

11

Start / End Page

1481 / 1493

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Triple Negative Breast Neoplasms
  • Signal Transduction
  • Receptor, Platelet-Derived Growth Factor beta
  • Receptor, Platelet-Derived Growth Factor alpha
  • Protein Kinase Inhibitors
  • Phosphorylation
  • Phosphoinositide-3 Kinase Inhibitors
  • Oncology & Carcinogenesis
 

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Van Swearingen, A. E. D., Sambade, M. J., Siegel, M. B., Sud, S., McNeill, R. S., Bevill, S. M., … Anders, C. K. (2017). Combined kinase inhibitors of MEK1/2 and either PI3K or PDGFR are efficacious in intracranial triple-negative breast cancer. Neuro-Oncology, 19(11), 1481–1493. https://doi.org/10.1093/neuonc/nox052
Van Swearingen, Amanda E. D., Maria J. Sambade, Marni B. Siegel, Shivani Sud, Robert S. McNeill, Samantha M. Bevill, Xin Chen, et al. “Combined kinase inhibitors of MEK1/2 and either PI3K or PDGFR are efficacious in intracranial triple-negative breast cancer.Neuro-Oncology 19, no. 11 (October 2017): 1481–93. https://doi.org/10.1093/neuonc/nox052.
Van Swearingen AED, Sambade MJ, Siegel MB, Sud S, McNeill RS, Bevill SM, et al. Combined kinase inhibitors of MEK1/2 and either PI3K or PDGFR are efficacious in intracranial triple-negative breast cancer. Neuro-oncology. 2017 Oct;19(11):1481–93.
Van Swearingen, Amanda E. D., et al. “Combined kinase inhibitors of MEK1/2 and either PI3K or PDGFR are efficacious in intracranial triple-negative breast cancer.Neuro-Oncology, vol. 19, no. 11, Oct. 2017, pp. 1481–93. Epmc, doi:10.1093/neuonc/nox052.
Van Swearingen AED, Sambade MJ, Siegel MB, Sud S, McNeill RS, Bevill SM, Chen X, Bash RE, Mounsey L, Golitz BT, Santos C, Deal A, Parker JS, Rashid N, Miller CR, Johnson GL, Anders CK. Combined kinase inhibitors of MEK1/2 and either PI3K or PDGFR are efficacious in intracranial triple-negative breast cancer. Neuro-oncology. 2017 Oct;19(11):1481–1493.
Journal cover image

Published In

Neuro-oncology

DOI

EISSN

1523-5866

ISSN

1522-8517

Publication Date

October 2017

Volume

19

Issue

11

Start / End Page

1481 / 1493

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Triple Negative Breast Neoplasms
  • Signal Transduction
  • Receptor, Platelet-Derived Growth Factor beta
  • Receptor, Platelet-Derived Growth Factor alpha
  • Protein Kinase Inhibitors
  • Phosphorylation
  • Phosphoinositide-3 Kinase Inhibitors
  • Oncology & Carcinogenesis