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.
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The EGFR inhibitors gefitinib and erlotinib have failed to demonstrate efficacy in GBM, largely as a consequence of persistent PI3K signaling due to PTEN loss and/or coactivation of other receptor tyrosine kinases.
“Despite the compelling nature of EGFR as a drug target in GBM, the EGFR inhibitors gefitinib and erlotinib have failed to demonstrate efficacy (9–11), in large part as a consequence of persistent PI3K signaling due to PTEN loss and/or coactivation of other receptor tyrosine kinases (9, 10, 12).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [12]
On p. 1, the paper reports that PTEN loss can make EGFR inhibitors ineffective by sustaining PI3K activity and proposes that inputs from other RTKs may also limit their efficacy. Its cell-line experiments on p. 2 show that combined RTK inhibition suppresses signaling where single-agent inhibition does not. The paper does not establish that these mechanisms are largely responsible for gefitinib and erlotinib's lack of clinical efficacy in GBM; it presents the broader clinical explanation as a possibility. (LLM, conf=0.83)
Experimental — accuracy not yet measuredOther RTKs that can be co-expressed in GBM, including c-MET, PDGFR-alpha and PDGFR-beta, can also engage PI3K signaling, resulting in EGFR inhibitor resistance.
“However, other RTKs that can be co-expressed in GBM, including some that may be upregulated after EGFR inhibitor therapies, like c-MET, PDGFR-alpha and PDGFR-beta, can also engage PI3K signaling, resulting in EGFR inhibitor resistance (12).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [12]
The paper reports co-activated MET and PDGFRs in GBM and shows that multiple RTKs can maintain PI3K signaling despite EGFR inhibition (pp. 1–2). It does not establish the citing sentence’s additional suggestion that these RTKs may be upregulated after EGFR inhibitor therapy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredOther PI3K pathway activating lesions commonly found in GBM, such as activation of other RTKs, could also promote increased LDLR expression.
“Therefore, other PI3K pathway activating lesions commonly found in GBM, such as the activation of other RTKs (6, 12, 39), could also promote increased LDLR expression.”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [12]
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Self-citation
- Authors
- Stommel, J. M., Kimmelman, A. C., Ying, H., Nabioullin, R., Ponugoti, A. H., Wiedemeyer, R., Stegh, A. H., Bradner, J. E., Ligon, K. L., Brennan, C., Chin, L., & DePinho, R. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- DePinho, Ronald A.
- ORCID
- Venue
- Science
- Published
- 2007-10-12
- Volume
- 318
- Issue
- 5848
- Pages
- 287-290
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1966803171
- Cited by
- 938
- References
- 1
- Citations by year
- 2026: 17 · 2025: 16 · 2024: 14 · 2023: 43 · 2022: 18 · 2021: 25 · 2020: 21 · 2019: 35 · 2018: 30 · 2017: 39 · 2016: 36 · 2015: 60 · 2014: 78 · 2013: 73 · 2012: 80
- FWCI
- 43.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01 CA99041, R01CA099041, 5P01CA95616, P01CA095616)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- receptor tyrosine kinase, PI3K signaling, glioblastoma, glioma, targeted therapy, RNA interference, PTEN loss, anchorage-independent growth, tumor cell survival
- MeSH terms
- Erlotinib Hydrochloride, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Brain Neoplasms, Cell Survival, Enzyme Activation, Glioblastoma, Humans, Indoles, Phosphorylation, Piperazines, Proto-Oncogene Proteins, Quinazolines, Sulfonamides, Signal Transduction, Receptors, Growth Factor, Proto-Oncogene Proteins c-met, Phosphatidylinositol 3-Kinases, Receptor Protein-Tyrosine Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, PTEN Phosphohydrolase, ErbB Receptors
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