Inhibition of epidermal growth factor receptor (EGFR) signaling is an important approach to the targeted treatment of cancer. However, although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is primarily effective only in a limited number of lung cancers that express specific EGFR mutations and are oncogene addicted. Thus, the ability to render cancer cells with primary EGFR resistance sensitive to EGFR inhibition is potentially of enormous clinical value, given the wide prevalence of EGFR overexpressing cancers with primary resistance to EGFR inhibition. EGFR wild type (EGFRwt) is the most common EGFR type expressed in human cancer. However, tumors expressing EGFRwt are not oncogene addicted and EGFR inhibition is generally ineffective as a treatment. Here, we propose a mechanism that mediates primary resistance to Erlotinib in glioblastoma (GBM) cells and a strategy to overcome it. EGFR gene amplification and mutation are common in GBM, but EGFR inhibition has not been effective in treating this tumor. We propose that the primary resistance of EGFR overexpressing GBMs results from a rapid adaptive response that prevents cell death from a sudden loss of EGFR signaling. This adaptive response can be detected in glioma cells expressing either EGFRwt or the oncogenic EGFRvIII mutant. Our preliminary data indicate that in glioma cells expressing either EGFRwt or EGFRvIII, Erlotinib triggers a rapid homeostatic response that involves activation of the RTK Axl and downstream activation of ERK. We propose that JNK acts as a master regulator of Erlotinib-triggered survival signals. Thus, Erlotinib exposure leads to increased TNF secretion, leading to activation of JNK. JNK activation leads to activation of Axl via increased secretion of GAS6, the ligand for Axl, and Axl induced ERK activation. Thus, we propose that primary resistance to EGFR inhibition in glioma cells results from activation of a TNF-JNK-Axl-ERK pathway.
In Specific Aim 1 : We elucidate the mechanism of Erlotinib-induced JNK activation. Erlotinib induced JNK activation is important because JNK triggers key survival signals as a response to EGFR inhibition. WE hypothesize that TNF plays a key role in Erlotinib induced JNK activation.
In Specific Aim 2 we examine the mechanisms mediating primary resistance to Erlotinib in glioma cells and examine the hypothesis that JNK activation results in activation the receptor tyrosine kinase Axl and downstream activation of ERK, and that this JNK-Axl-ERK axis mediates primary resistance to Erlotinib.
In Specific Aim 3 we examine the biological effect of combined inhibition of EGFR and TNF or JNK or Axl in a preclinical mouse model examining the hypothesis that interruption of adaptive survival signaling triggered by EGFR inhibition will transform cancers with primary resistance into cancers that can be effectively treated by EGFR inhibition. Since both EGFR and TNF inhibitors are in clinical use, this approach could be rapidly tested in patients.

Public Health Relevance

The epidermal growth factor receptor (EGFR) promotes growth of malignant cells. However, inhibition of the EGFR does not inhibit growth in most cancers, including glioblastoma. We aim to improve understanding of mechanisms of resistance to EGFR inhibition in glioblastoma and examine a strategy to overcome the resistance of glioma cells to EGFR inhibition. This strategy could prove to be an new treatment option for glioblastoma.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Oncology E (ONCE)
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VA North Texas Health Care System
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Newman, Jennifer P; Wang, Grace Y; Arima, Kazuhiko et al. (2017) Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme. Nat Commun 8:1913
Wang, Lulu; Habib, Amyn A; Mintz, Akiva et al. (2017) Phosphatidylserine-Targeted Nanotheranostics for Brain Tumor Imaging and Therapeutic Potential. Mol Imaging 16:1536012117708722
Guo, Gao; Gong, Ke; Ali, Sonia et al. (2017) A TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma. Nat Neurosci 20:1074-1084
Gil Del Alcazar, Carlos Rodrigo; Todorova, Pavlina Krasimirova; Habib, Amyn A et al. (2016) Augmented HR Repair Mediates Acquired Temozolomide Resistance in Glioblastoma. Mol Cancer Res 14:928-940
Zhang, Liang; Habib, Amyn A; Zhao, Dawen (2016) Phosphatidylserine-targeted liposome for enhanced glioma-selective imaging. Oncotarget 7:38693-38706
Guo, Gao; Gong, Ke; Wohlfeld, Bryan et al. (2015) Ligand-Independent EGFR Signaling. Cancer Res 75:3436-41
Chakraborty, Sharmistha; Li, Li; Puliyappadamba, Vineshkumar Thidil et al. (2014) Constitutive and ligand-induced EGFR signalling triggers distinct and mutually exclusive downstream signalling networks. Nat Commun 5:5811