Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma

Robert S. McNeill, Demitra A. Canoutas, Timothy J. Stuhlmiller, Harshil D. Dhruv, David M. Irvin, Ryan E. Bash, Steven P. Angus, Laura E. Herring, Jeremy M. Simon, Kasey R. Skinner, Juanita C. Limas, Xin Chen, Ralf S. Schmid, Marni B. Siegel, Amanda E.D. Van Swearingen, Michael J. Hadler, Erik P. Sulman, Jann N Sarkaria, Carey K. Anders, Lee M. Graves & 3 others Michael E. Berens, Gary L. Johnson, C. Ryan Miller

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background. Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Prognosis remains poor despite multimodal therapy. Developing alternative treatments is essential. Drugs targeting kinases within the phosphoinositide 3-kinase (PI3K) and mitogen-Activated protein kinase (MAPK) effectors of receptor tyrosine kinase (RTK) signaling represent promising candidates. Methods. We previously developed a non-germline genetically engineered mouse model of GBM in which PI3K and MAPK are activated via Pten deletion and KrasG12D in immortalized astrocytes. Using this model, we examined the influence of drug potency on target inhibition, alternate pathway activation, efficacy, and synergism of single agent and combination therapy with inhibitors of these 2 pathways. Efficacy was then examined in GBM patient-derived xenografts (PDX) in vitro and in vivo. Results. PI3K and mitogen-Activated protein kinase kinase (MEK) inhibitor potency was directly associated with target inhibition, alternate RTK effector activation, and efficacy in mutant murine astrocytes in vitro. The kinomes of GBM PDX and tumor samples were heterogeneous, with a subset of the latter harboring MAPK hyperactivation. Dual PI3K/MEK inhibitor treatment overcame alternate effector activation, was synergistic in vitro, and was more effective than single agent therapy in subcutaneous murine allografts. However, efficacy in orthotopic allografts was minimal. This was likely due to dose-limiting toxicity and incomplete target inhibition. Conclusion. Drug potency influences PI3K/MEK inhibitor-induced target inhibition, adaptive kinome reprogramming, efficacy, and synergy. Our findings suggest that combination therapies with highly potent, brain-penetrant kinase inhibitors will be required to improve patient outcomes.

Original languageEnglish (US)
Pages (from-to)1469-1480
Number of pages12
JournalNeuro-Oncology
Volume19
Issue number11
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

Fingerprint

1-Phosphatidylinositol 4-Kinase
Glioblastoma
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase Kinases
Receptor Protein-Tyrosine Kinases
Heterografts
Astrocytes
Allografts
Phosphotransferases
Therapeutics
MAP Kinase Kinase Kinases
Drug Delivery Systems
Brain Neoplasms
Pharmaceutical Preparations
Brain
In Vitro Techniques
Neoplasms

Keywords

  • Genetically engineered mice
  • Glioblastoma
  • Kinase inhibitors
  • MAPK
  • PI3K

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

McNeill, R. S., Canoutas, D. A., Stuhlmiller, T. J., Dhruv, H. D., Irvin, D. M., Bash, R. E., ... Miller, C. R. (2017). Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma. Neuro-Oncology, 19(11), 1469-1480. https://doi.org/10.1093/neuonc/nox044

Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma. / McNeill, Robert S.; Canoutas, Demitra A.; Stuhlmiller, Timothy J.; Dhruv, Harshil D.; Irvin, David M.; Bash, Ryan E.; Angus, Steven P.; Herring, Laura E.; Simon, Jeremy M.; Skinner, Kasey R.; Limas, Juanita C.; Chen, Xin; Schmid, Ralf S.; Siegel, Marni B.; Van Swearingen, Amanda E.D.; Hadler, Michael J.; Sulman, Erik P.; Sarkaria, Jann N; Anders, Carey K.; Graves, Lee M.; Berens, Michael E.; Johnson, Gary L.; Miller, C. Ryan.

In: Neuro-Oncology, Vol. 19, No. 11, 01.11.2017, p. 1469-1480.

Research output: Contribution to journalArticle

McNeill, RS, Canoutas, DA, Stuhlmiller, TJ, Dhruv, HD, Irvin, DM, Bash, RE, Angus, SP, Herring, LE, Simon, JM, Skinner, KR, Limas, JC, Chen, X, Schmid, RS, Siegel, MB, Van Swearingen, AED, Hadler, MJ, Sulman, EP, Sarkaria, JN, Anders, CK, Graves, LM, Berens, ME, Johnson, GL & Miller, CR 2017, 'Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma', Neuro-Oncology, vol. 19, no. 11, pp. 1469-1480. https://doi.org/10.1093/neuonc/nox044
McNeill, Robert S. ; Canoutas, Demitra A. ; Stuhlmiller, Timothy J. ; Dhruv, Harshil D. ; Irvin, David M. ; Bash, Ryan E. ; Angus, Steven P. ; Herring, Laura E. ; Simon, Jeremy M. ; Skinner, Kasey R. ; Limas, Juanita C. ; Chen, Xin ; Schmid, Ralf S. ; Siegel, Marni B. ; Van Swearingen, Amanda E.D. ; Hadler, Michael J. ; Sulman, Erik P. ; Sarkaria, Jann N ; Anders, Carey K. ; Graves, Lee M. ; Berens, Michael E. ; Johnson, Gary L. ; Miller, C. Ryan. / Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma. In: Neuro-Oncology. 2017 ; Vol. 19, No. 11. pp. 1469-1480.
@article{2eda43fb9bd74d0ea24db39c8f9b77da,
title = "Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma",
abstract = "Background. Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Prognosis remains poor despite multimodal therapy. Developing alternative treatments is essential. Drugs targeting kinases within the phosphoinositide 3-kinase (PI3K) and mitogen-Activated protein kinase (MAPK) effectors of receptor tyrosine kinase (RTK) signaling represent promising candidates. Methods. We previously developed a non-germline genetically engineered mouse model of GBM in which PI3K and MAPK are activated via Pten deletion and KrasG12D in immortalized astrocytes. Using this model, we examined the influence of drug potency on target inhibition, alternate pathway activation, efficacy, and synergism of single agent and combination therapy with inhibitors of these 2 pathways. Efficacy was then examined in GBM patient-derived xenografts (PDX) in vitro and in vivo. Results. PI3K and mitogen-Activated protein kinase kinase (MEK) inhibitor potency was directly associated with target inhibition, alternate RTK effector activation, and efficacy in mutant murine astrocytes in vitro. The kinomes of GBM PDX and tumor samples were heterogeneous, with a subset of the latter harboring MAPK hyperactivation. Dual PI3K/MEK inhibitor treatment overcame alternate effector activation, was synergistic in vitro, and was more effective than single agent therapy in subcutaneous murine allografts. However, efficacy in orthotopic allografts was minimal. This was likely due to dose-limiting toxicity and incomplete target inhibition. Conclusion. Drug potency influences PI3K/MEK inhibitor-induced target inhibition, adaptive kinome reprogramming, efficacy, and synergy. Our findings suggest that combination therapies with highly potent, brain-penetrant kinase inhibitors will be required to improve patient outcomes.",
keywords = "Genetically engineered mice, Glioblastoma, Kinase inhibitors, MAPK, PI3K",
author = "McNeill, {Robert S.} and Canoutas, {Demitra A.} and Stuhlmiller, {Timothy J.} and Dhruv, {Harshil D.} and Irvin, {David M.} and Bash, {Ryan E.} and Angus, {Steven P.} and Herring, {Laura E.} and Simon, {Jeremy M.} and Skinner, {Kasey R.} and Limas, {Juanita C.} and Xin Chen and Schmid, {Ralf S.} and Siegel, {Marni B.} and {Van Swearingen}, {Amanda E.D.} and Hadler, {Michael J.} and Sulman, {Erik P.} and Sarkaria, {Jann N} and Anders, {Carey K.} and Graves, {Lee M.} and Berens, {Michael E.} and Johnson, {Gary L.} and Miller, {C. Ryan}",
year = "2017",
month = "11",
day = "1",
doi = "10.1093/neuonc/nox044",
language = "English (US)",
volume = "19",
pages = "1469--1480",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "11",

}

TY - JOUR

T1 - Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma

AU - McNeill, Robert S.

AU - Canoutas, Demitra A.

AU - Stuhlmiller, Timothy J.

AU - Dhruv, Harshil D.

AU - Irvin, David M.

AU - Bash, Ryan E.

AU - Angus, Steven P.

AU - Herring, Laura E.

AU - Simon, Jeremy M.

AU - Skinner, Kasey R.

AU - Limas, Juanita C.

AU - Chen, Xin

AU - Schmid, Ralf S.

AU - Siegel, Marni B.

AU - Van Swearingen, Amanda E.D.

AU - Hadler, Michael J.

AU - Sulman, Erik P.

AU - Sarkaria, Jann N

AU - Anders, Carey K.

AU - Graves, Lee M.

AU - Berens, Michael E.

AU - Johnson, Gary L.

AU - Miller, C. Ryan

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Background. Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Prognosis remains poor despite multimodal therapy. Developing alternative treatments is essential. Drugs targeting kinases within the phosphoinositide 3-kinase (PI3K) and mitogen-Activated protein kinase (MAPK) effectors of receptor tyrosine kinase (RTK) signaling represent promising candidates. Methods. We previously developed a non-germline genetically engineered mouse model of GBM in which PI3K and MAPK are activated via Pten deletion and KrasG12D in immortalized astrocytes. Using this model, we examined the influence of drug potency on target inhibition, alternate pathway activation, efficacy, and synergism of single agent and combination therapy with inhibitors of these 2 pathways. Efficacy was then examined in GBM patient-derived xenografts (PDX) in vitro and in vivo. Results. PI3K and mitogen-Activated protein kinase kinase (MEK) inhibitor potency was directly associated with target inhibition, alternate RTK effector activation, and efficacy in mutant murine astrocytes in vitro. The kinomes of GBM PDX and tumor samples were heterogeneous, with a subset of the latter harboring MAPK hyperactivation. Dual PI3K/MEK inhibitor treatment overcame alternate effector activation, was synergistic in vitro, and was more effective than single agent therapy in subcutaneous murine allografts. However, efficacy in orthotopic allografts was minimal. This was likely due to dose-limiting toxicity and incomplete target inhibition. Conclusion. Drug potency influences PI3K/MEK inhibitor-induced target inhibition, adaptive kinome reprogramming, efficacy, and synergy. Our findings suggest that combination therapies with highly potent, brain-penetrant kinase inhibitors will be required to improve patient outcomes.

AB - Background. Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Prognosis remains poor despite multimodal therapy. Developing alternative treatments is essential. Drugs targeting kinases within the phosphoinositide 3-kinase (PI3K) and mitogen-Activated protein kinase (MAPK) effectors of receptor tyrosine kinase (RTK) signaling represent promising candidates. Methods. We previously developed a non-germline genetically engineered mouse model of GBM in which PI3K and MAPK are activated via Pten deletion and KrasG12D in immortalized astrocytes. Using this model, we examined the influence of drug potency on target inhibition, alternate pathway activation, efficacy, and synergism of single agent and combination therapy with inhibitors of these 2 pathways. Efficacy was then examined in GBM patient-derived xenografts (PDX) in vitro and in vivo. Results. PI3K and mitogen-Activated protein kinase kinase (MEK) inhibitor potency was directly associated with target inhibition, alternate RTK effector activation, and efficacy in mutant murine astrocytes in vitro. The kinomes of GBM PDX and tumor samples were heterogeneous, with a subset of the latter harboring MAPK hyperactivation. Dual PI3K/MEK inhibitor treatment overcame alternate effector activation, was synergistic in vitro, and was more effective than single agent therapy in subcutaneous murine allografts. However, efficacy in orthotopic allografts was minimal. This was likely due to dose-limiting toxicity and incomplete target inhibition. Conclusion. Drug potency influences PI3K/MEK inhibitor-induced target inhibition, adaptive kinome reprogramming, efficacy, and synergy. Our findings suggest that combination therapies with highly potent, brain-penetrant kinase inhibitors will be required to improve patient outcomes.

KW - Genetically engineered mice

KW - Glioblastoma

KW - Kinase inhibitors

KW - MAPK

KW - PI3K

UR - http://www.scopus.com/inward/record.url?scp=85029659907&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029659907&partnerID=8YFLogxK

U2 - 10.1093/neuonc/nox044

DO - 10.1093/neuonc/nox044

M3 - Article

VL - 19

SP - 1469

EP - 1480

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 11

ER -