Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies

Jayne M. Stommel, Alec C. Kimmelman, Haoqiang Ying, Roustem Nabioullin, Aditya H. Ponugoti, Ruprecht Wiedemeyer, Alexander H. Stegh, James E. Bradner, Keith L. Ligon, Cameron Brennan, Lynda Chin, Ronald A. DePinho*

*Corresponding author for this work

Research output: Contribution to journalArticle

688 Citations (Scopus)

Abstract

Targeted therapies that inhibit receptor tyrosine kinases (RTKs) and the downstream phosphatidylinositol 3-kinase (PI3K) signaling pathway have shown promising anticancer activity, but their efficacy in the brain tumor glioblastoma multiforme (GBM) and other solid tumors has been modest. We hypothesized that multiple RTKs are coactivated in these tumors and that redundant inputs drive and maintain downstream signaling, thereby limiting the efficacy of therapies targeting single RTKs. Tumor cell lines, xenotransplants, and primary tumors indeed show multiple concomitantly activated RTKs. Combinations of RTK inhibitors and/or RNA interference, but not single agents, decreased signaling, cell survival, and anchorage-independent growth even in glioma cells deficient in PTEN, a frequently inactivated inhibitor of PI3K. Thus, effective GBM therapy may require combined regimens targeting multiple RTKs.

Original languageEnglish (US)
Pages (from-to)287-290
Number of pages4
JournalScience
Volume318
Issue number5848
DOIs
StatePublished - Oct 12 2007

Fingerprint

Receptor Protein-Tyrosine Kinases
Phosphatidylinositol 3-Kinase
Neoplasms
Glioblastoma
Therapeutics
RNA Interference
Tumor Cell Line
Brain Neoplasms
Glioma
Cell Survival
Growth

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Stommel, J. M., Kimmelman, A. C., Ying, H., Nabioullin, R., Ponugoti, A. H., Wiedemeyer, R., ... DePinho, R. A. (2007). Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science, 318(5848), 287-290. https://doi.org/10.1126/science.1142946
Stommel, Jayne M. ; Kimmelman, Alec C. ; Ying, Haoqiang ; Nabioullin, Roustem ; Ponugoti, Aditya H. ; Wiedemeyer, Ruprecht ; Stegh, Alexander H. ; Bradner, James E. ; Ligon, Keith L. ; Brennan, Cameron ; Chin, Lynda ; DePinho, Ronald A. / Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. In: Science. 2007 ; Vol. 318, No. 5848. pp. 287-290.
@article{e2f3282c3d3e4ef190c89b71dd34a440,
title = "Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies",
abstract = "Targeted therapies that inhibit receptor tyrosine kinases (RTKs) and the downstream phosphatidylinositol 3-kinase (PI3K) signaling pathway have shown promising anticancer activity, but their efficacy in the brain tumor glioblastoma multiforme (GBM) and other solid tumors has been modest. We hypothesized that multiple RTKs are coactivated in these tumors and that redundant inputs drive and maintain downstream signaling, thereby limiting the efficacy of therapies targeting single RTKs. Tumor cell lines, xenotransplants, and primary tumors indeed show multiple concomitantly activated RTKs. Combinations of RTK inhibitors and/or RNA interference, but not single agents, decreased signaling, cell survival, and anchorage-independent growth even in glioma cells deficient in PTEN, a frequently inactivated inhibitor of PI3K. Thus, effective GBM therapy may require combined regimens targeting multiple RTKs.",
author = "Stommel, {Jayne M.} and Kimmelman, {Alec C.} and Haoqiang Ying and Roustem Nabioullin and Ponugoti, {Aditya H.} and Ruprecht Wiedemeyer and Stegh, {Alexander H.} and Bradner, {James E.} and Ligon, {Keith L.} and Cameron Brennan and Lynda Chin and DePinho, {Ronald A.}",
year = "2007",
month = "10",
day = "12",
doi = "10.1126/science.1142946",
language = "English (US)",
volume = "318",
pages = "287--290",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "5848",

}

Stommel, JM, Kimmelman, AC, Ying, H, Nabioullin, R, Ponugoti, AH, Wiedemeyer, R, Stegh, AH, Bradner, JE, Ligon, KL, Brennan, C, Chin, L & DePinho, RA 2007, 'Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies', Science, vol. 318, no. 5848, pp. 287-290. https://doi.org/10.1126/science.1142946

Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. / Stommel, Jayne M.; Kimmelman, Alec C.; Ying, Haoqiang; Nabioullin, Roustem; Ponugoti, Aditya H.; Wiedemeyer, Ruprecht; Stegh, Alexander H.; Bradner, James E.; Ligon, Keith L.; Brennan, Cameron; Chin, Lynda; DePinho, Ronald A.

In: Science, Vol. 318, No. 5848, 12.10.2007, p. 287-290.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies

AU - Stommel, Jayne M.

AU - Kimmelman, Alec C.

AU - Ying, Haoqiang

AU - Nabioullin, Roustem

AU - Ponugoti, Aditya H.

AU - Wiedemeyer, Ruprecht

AU - Stegh, Alexander H.

AU - Bradner, James E.

AU - Ligon, Keith L.

AU - Brennan, Cameron

AU - Chin, Lynda

AU - DePinho, Ronald A.

PY - 2007/10/12

Y1 - 2007/10/12

N2 - Targeted therapies that inhibit receptor tyrosine kinases (RTKs) and the downstream phosphatidylinositol 3-kinase (PI3K) signaling pathway have shown promising anticancer activity, but their efficacy in the brain tumor glioblastoma multiforme (GBM) and other solid tumors has been modest. We hypothesized that multiple RTKs are coactivated in these tumors and that redundant inputs drive and maintain downstream signaling, thereby limiting the efficacy of therapies targeting single RTKs. Tumor cell lines, xenotransplants, and primary tumors indeed show multiple concomitantly activated RTKs. Combinations of RTK inhibitors and/or RNA interference, but not single agents, decreased signaling, cell survival, and anchorage-independent growth even in glioma cells deficient in PTEN, a frequently inactivated inhibitor of PI3K. Thus, effective GBM therapy may require combined regimens targeting multiple RTKs.

AB - Targeted therapies that inhibit receptor tyrosine kinases (RTKs) and the downstream phosphatidylinositol 3-kinase (PI3K) signaling pathway have shown promising anticancer activity, but their efficacy in the brain tumor glioblastoma multiforme (GBM) and other solid tumors has been modest. We hypothesized that multiple RTKs are coactivated in these tumors and that redundant inputs drive and maintain downstream signaling, thereby limiting the efficacy of therapies targeting single RTKs. Tumor cell lines, xenotransplants, and primary tumors indeed show multiple concomitantly activated RTKs. Combinations of RTK inhibitors and/or RNA interference, but not single agents, decreased signaling, cell survival, and anchorage-independent growth even in glioma cells deficient in PTEN, a frequently inactivated inhibitor of PI3K. Thus, effective GBM therapy may require combined regimens targeting multiple RTKs.

UR - http://www.scopus.com/inward/record.url?scp=35348822482&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35348822482&partnerID=8YFLogxK

U2 - 10.1126/science.1142946

DO - 10.1126/science.1142946

M3 - Article

C2 - 17872411

AN - SCOPUS:35348822482

VL - 318

SP - 287

EP - 290

JO - Science

JF - Science

SN - 0036-8075

IS - 5848

ER -

Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science. 2007 Oct 12;318(5848):287-290. https://doi.org/10.1126/science.1142946