Current Research

EGFR signaling in temozolomide resistance in glioblastoma

Temozolomide (TMZ), an alkylating agent, is the first line chemotherapeutic drug for patients with glioblastoma (GBM). Unfortunately, over half of patients do not respond, and even those who do respond initially can develop resistance and suffer early disease recurrence. There is no effective treatment for recurrent TMZ resistant GBM. The DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT) enables cells to reverse the cytotoxicity of TMZ, representing one of the well-documented mechanisms in GBM resistance. This underscores the potential efficacy of reducing MGMT expression as a promising therapeutic strategy for TMZ resistant GBM patients. 

Epidermal growth factor receptor (EGFR) is the most frequently amplified and mutated oncogene in GBM.  Over 80% of human GBM tissues exhibit positive staining for EGFR. We have found that EGFR tyrosine kinase inhibitor (TKI) reduces MGMT expression at both protein and mRNA levels in multiple primary and secondary TMZ resistant patient derived xenograft (PDX) cell lines. Our data further show that a complex signaling network involving Activator protein 1 (AP-1) and microRNAs participates in EGFR inhibition induced MGMT downregulation. Our hypothesis is that EGFR inhibition overcomes TMZ resistance through reducing MGMT expression. To confirm the hypothesis, we aim to investigate the mechanism of MGMT downregulation driven by EGFR inhibition. Additionally, we will assess the efficacy of combining EGFR TKIs with TMZ in multiple preclinical mouse models of TMZ resistant GBM. 

Characterization of signaling pathways involved in collagen production in glioblastoma 

Collagen expression is low in normal brain, while the content of collagen increases in glioma environment especially in perivascular regions.  Studies have shown that collagen plays an important role in angiogenesis of GBM and is implicated in GBM progression by promoting invasion, inhibiting apoptosis and stemness maintenance of glioblastoma cells. The overexpression of collagen has been correlated with poor survival of GBM patients. However, little is known about the upstream signaling pathways regulating collagen production in GBM. In this study, we will use comprehensive molecular techniques, such as single cell RNA sequencing and cell-cell communication analysis, to characterize the signaling pathways responsible for collagen remodeling. We will use both PDX cell lines and preclinical mouse models to explore the crosstalk between EGFR and other kinase signaling pathways and their impact on collagen production in GBM.

Select Publications

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  • Guo G , Gong K, Beckley N, Zhang Y, Yang X , Chkheidze R, Hatanpaa KJ , Garzon-Muvdi T , Koduru P , Nayab A , Jenks J , Amod Sathe A, Liu Y , Xing C, Wu  S, Chiang C, Mukherjee B, Burma S, Wohlfeld B , Patel T, Mickey B, Abdullah K, Youssef M, Pan E, Gerber DE, Tian S, Sarkaria JN, McBrayer SK, Zhao D,  Habib AA. EGFR ligand shifts the role of EGFR from oncogene to tumor suppressor in EGFR amplified glioblastoma. Nat Cell Biol. 2022;24:1291-1305.
  • Gong K, Guo G, Beckley N, Yang X, Zhang Y, Gerber DE, Minna JD, Burma S, Zhao D, Akbay EA, Habib AA. Comprehensive targeting of resistance to inhibition of RTK signaling pathways by using glucocorticoids. Nat Commun.2021;12(1):7014.
  • Guo G, Gong K, Puliyappadamba VT, Panchani N, Pan E, Mukherjee B, Damanwalla Z, Bharia S, Hatanpaa KJ, Gerber DE, Mickey BE, Patel TR, Sarkaria JN, Zhao D, Burma S, Habib AA.  Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma. Neuro Oncol. 2019; 21(12):1529-1539.
  • Gong K*, Guo G*, Gerber DE, Gao B, Peyton M, Huang C, Minna JD, Hatanpaa KJ, Kernstine K, Cai L, Xie Y, Zhu H, Fattah FJ, Zhang S, Takahashi M, Mukherjee B, Burma S, Dowell J, Dao K, Papadimitrakopoulou VA,  Olivas V, Bivona TG, Zhao D, Habib AA.  TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer.  J Clin Invest. 2018;128(6):2500-2518. *Contributed equally
  • Guo G, Gong K, Ali S, Ali N, Shallwani S, Hatanpaa KJ, Pan E, Mickey B, Burma S, Wang DH, Kesari S, Sarkaria JN, Zhao D, Habib AA. TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma. Nat Neurosci. 2017 ; 20(8):1074-1084. Highlighted in News and Views article:  Warta R, Herold-Mende C. Helping EGFR inhibition to block cancer.  Nat  Neurosci. 2017 Aug; 20(8):1035-1037.
  • Guo G, Gong K, Wohlfeld B, Hatanpaa KJ, Zhao D, Habib AA. Ligand-independent EGFR signaling. Cancer Res.  2015;75(17):3436-41.
  • Guo G, Muñoz-García B, Ott CE, Grünhagen J, Mousa SA, Pletschacher A, von Kodolitsch Y, Knaus P, Robinson PN. Antagonism of GxxPG-fragments ameliorates manifestations of aortic disease in Marfan syndrome mice. Hum Mol Genet. 2013;22(3):433-43
  • Guo G, Booms P, Halushka M, Dietz HC, Ney A, Stricker S, Hecht J, Mundlos S, Robinson PN. Induction of macrophage chemotaxis by aortic extracts of the mgR Marfan mouse model and a GxxPG-containing fibrillin-1 fragment. Circulation. 2006;114(17):1855-62.