Our laboratory is interested in improving treatment for patients with glioblastoma (GBM) and other cancers. We work on understanding signal transduction pathways involved in the pathogenesis of cancer. Recent work has focused on investigating mechanisms of resistance to targeted treatment in GBM and lung cancer. We are also interested in mechanisms regulating invasion in GBM.
Identification of an adaptive mechanism that mediates primary resistance to EGFR inhibition in GBM:
EGFR gene amplification and mutation is a signature lesion in GBM resulting in increased expression of EGFR wild type (EGFRwt) and oncogenic mutant forms of the EGFR such as EGFRvIII. Furthermore, experimental evidence suggests an important role for both EGFRvIII and EGFRwt in gliomagenesis. Thus, the EGFR is considered an important target in GBM. However, EGFR inhibition using tyrosine kinase inhibitors has not been successful in improving the survival of GBM patients. We have recently found that inhibition of the EGFR receptor in an experimental model of glioma resulted in activation of an adaptive response that protected glioma cells from a loss of EGFR signaling. Inhibition of this adaptive signaling response resulted in enhanced sensitivity to EGFR inhibition. Our initial studies suggested that a TNF-JNK-Axl-ERK signaling pathway mediates primary resistance to EGFR inhibition in GBM cells. In a subsequent study we compared the efficacy of a combined EGFR plus TNF inhibition to temozolomide (TMZ), the standard of care treatment in GBM. We found that EGFR plus TNF inhibition is more effective compared to TMZ in large subsets of GBMs.
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, and Habib AA. A TNF–JNK–Axl–ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma. Nat Neurosci. 2017 Aug;20(8):1074-1084. doi: 10.1038/nn.4584. Epub 2017 Jun 12. PMCID: PMC5529219
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, and Habib AA. Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma. Neuro Oncol. 2019 Dec 17;21(12):1529-1539. doi: 10.1093/neuonc/noz127.
Identification of adaptive mechanisms that mediate resistance to EGFR inhibition in lung cancer:
Aberrant EGFR signaling is common in non-small cell lung cancer (NSCLC). However, EGFR inhibition is effective only in tumors with EGFR activating mutations. We have found that EGFR inhibition triggers adaptive responses in both EGFRwt and EGFR mutant NSCLC, and provided evidence that these adaptive responses play a role in mediating both primary as well as secondary resistance in NSCLC. Our initial studies have suggested that a TNF- NF-kB signaling pathway mediates resistance to EGFR inhibition in NSCLC and that a combined inhibition of EGFR+TNF renders the majority of NSCLC sensitive to EGFR inhibition in a preclinical model, thus potentially expanding the reach and utility of EGFR inhibition in NSCLC greatly. More recently, we have found that EGFR inhibition triggers an adaptive response driven by co-optation of antiviral signaling pathways and induction of Type I IFNs that play a role in both primary and secondary resistance in NSCLC.
Gong K, Guo G, Panchani N, Bender ME, Gerber DE, Minna JD, Fattah F, Gao B, Peyton M, Kernstine K, Mukherjee B, Burma S, Chiang CM, Zhang S, Sathe AA, Xing C, Dao KH, Zhao D, Akbay EA, and Habib AA. EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer. Nat. Cancer 2020 1, 394
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, and Habib AA*. TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer. J Clin Invest. 2018 Jun 1;128(6):2500-2518. doi: 10.1172/JCI96148. Epub 2018 May 7.
Identification of bimodal EGFR signaling in cancer:
Aberrant EGFR signaling is widespread in cancer. However, EGFR signaling in cancer is still not well understood. When the EGFR is overexpressed it becomes tyrosine phosphorylated and constitutively active even in the absence of any exogenous ligand. While constitutive EGFR signaling has been reported, the downstream signals triggered by the EGFR in the absence of ligand are unclear. We demonstrated that constitutive and ligand induced EGFR signaling trigger distinct and mutually exclusive signaling networks. In the absence of ligand, the EGFR activates an IRF3 dependent transcription network.The EGFR does not activate canonical signals such as ERK and Akt unless EGF is added. The addition of EGF leads to a switching off IRF3 activity and triggering of ERK and Akt activity suggesting that constitutive and ligand induced signals are mutually exclusive. Mechanistically, the switch from constitutive to ligand activated signaling is accomplished by a change in the signaling proteins associated with the EGFR. Biologically, constitutive EGFR signaling protects from virus and chemotherapy induced cell death and may confer an advantage during the clonal evolution of tumors and promote resistance from chemotherapy. Thus, the EGFR oscillates between constitutive and ligand induced signaling programs depending on the availability of ligand in the tumor, and such oscillation may profoundly influence tumor growth and responsiveness to treatment. More recent work in our laboratory indicates that this oscillation may influence spatiotemporal regulation of proliferation and invasion in GBM.
Chakraborty S., Li L, Puliyappadamba VT, Guo G, Hatanpaa KJ, Mickey B, Souza RF, Vo P, Herz J, Chen MR, Boothman DA, Pandita TK, Wang DH, Sen GC, and Habib AA. Constitutive and ligand-induced EGFR signaling triggers distinct and mutually exclusive downstream signaling networks. Nat Commun. 2014 Dec 15;5:5811. doi: 10.1038/ncomms6811. PMCID: PMC4268886
Guo G, Gong K, Wohlfeld B, Hatanpaa K, Zhao D and Habib AA. Ligand-independent EGFR signaling Cancer Res. 2015 Sep 1;75(17):3436-41. PMCID: PMC4558210
Newman JP, Wang GY, Arima K, Guan SP, Waters MR, Cavenee WK, Pan E, Aliwarga E, Chong ST, Li KY, Endaya BB, Habib AA, Horibe T, Ng WH, Ho IAW, Hui KM, Kordula T, and Lam PYP. Interleukin-13 Receptor Alpha 2 (IL-13Rα2) cooperates with EGFRvIII signaling to promote Glioblastoma Multiforme Nat Commun 2017 Dec 4;8(1):1913. doi: 10.1038/s41467-017-01392-9.