Introduction: Receptor tyrosine kinases (RTK), such as c-Met and epidermal growth factor receptor (EGFR), are implicated in the malignant progression of glioblastoma. Studies show that RTK systems can co-modulate distinct and overlapping oncogenic downstream signaling pathways. EGFRvIII, a constitutively activated EGFR deletion mutant variant, leads to increased tumor growth and diminishes the tumor growth response to HGF:c-Met pathway inhibitor therapy. Conversely, activation of the c-Met pathway diminishes the tumor growth response to EGFR pathway inhibitors.
Methods: Previously we reported that EGFRvIII and c-Met pathway inhibitors synergize to inhibit tumor growth in isogenic GBM cell lines engineered to express EGFRvIII. To determine the broader relevance of these earlier findings, we examined the effects of combination c-Met and EGFR pathway inhibitor therapy on tumor growth responses, downstream second messenger systems, and stem-like tumor propogating cell populations in constitutively activated c-Met+/EGFRvIII+ primary human glioblastoma xenografts lines.
Results: We show that Crizotinib (c-Met pathway inhibitor) and Erlotinib (EGFR pathway inhibitor) in combination significantly inhibit tumor growth, phospho-EGFRvIII, phospho-Met, phospho-AKT, phospho-MAPK, and neurosphere growth in Mayo 39 and Mayo 59 primary GBM subcutaneous xenografts. The expression of the stem cell markers Nestin, Musashi, Olig 2 and Sox2 were also significantly down-regulated by c-Met inhibition, but no additive down-regulation was seen by co-treatment with Erlotinib.
Conclusions: These results are consistent with and corroborate our previous findings demonstrating that targeting these two parallel pathways with c-Met and EGFR inhibitor therapy provides substantial anti-tumor activity in glioblastoma models.
Patient Care: This research will improve patient care by demonstrating that targeting c-Met and EGFR pathways in glioblastoma xenograft models provides substantial anti-tumor activity.
Learning Objectives: By the conclusion of this session, participants should be able to describe the importance of the c-Met and EGFR pathway in glioblastoma and the benefit of targeting these two parallel pathways with c-Met and EGFR inhibitors in human glioblastoma xenograft models.
1. Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes & development. Nov 1 2007;21(21):2683-2710.
2. Karpel-Massler G, Schmidt U, Unterberg A, Halatsch ME. Therapeutic inhibition of the epidermal growth factor receptor in high-grade gliomas: where do we stand? Molecular cancer research : MCR. Jul 2009;7(7):1000-1012.
3. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. Mar 10 2005;352(10):987-996.
4. Lal B, Goodwin CR, Sang Y, et al. EGFRvIII and c-Met pathway inhibitors synergize against PTEN-null/EGFRvIII+ glioblastoma xenografts. Molecular cancer therapeutics. Jul 2009;8(7):1751-1760.
5. Raymond E, Brandes AA, Dittrich C, et al. Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group Study. J Clin Oncol. Oct 1 2008;26(28):4659-4665.
6. Lal B, Xia S, Abounader R, Laterra J. Targeting the c-Met pathway potentiates glioblastoma responses to gamma-radiation. Clin Cancer Res. Jun 15 2005;11(12):4479-4486.
7. Xu H, Stabile LP, Gubish CT, Gooding WE, Grandis JR, Siegfried JM. Dual blockade of EGFR and c-Met abrogates redundant signaling and proliferation in head and neck carcinoma cells. Clin Cancer Res. Jul 1 2011;17(13):4425-4438.
8. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. May 18 2007;316(5827):1039-1043.
9. Stommel JM, Kimmelman AC, Ying H, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science. Oct 12 2007;318(5848):287-290.
10. Liu X, Newton RC, Scherle PA. Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends in molecular medicine. Jan 2010;16(1):37-45.
11. Lo HW. Emerging therapeutic targets and agents for glioblastoma therapy--part II. Anti-cancer agents in medicinal chemistry. Sep 2010;10(7):511.
12. Carlson BL, Pokorny JL, Schroeder MA, Sarkaria JN. Establishment, maintenance and in vitro and in vivo applications of primary human glioblastoma multiforme (GBM) xenograft models for translational biology studies and drug discovery. Current protocols in pharmacology / editorial board, S.J. Enna. Mar 2011;Chapter 14:Unit 14 16.
13. Chi AS, Batchelor TT, Dias-Santagata D, et al. Prospective, high-throughput molecular profiling of human gliomas. Journal of neuro-oncology. Oct 2012;110(1):89-98.
14. Agarwal S, Zerillo C, Kolmakova J, et al. Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells. British journal of cancer. Mar 24 2009;100(6):941-949.
15. Turke AB, Zejnullahu K, Wu YL, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer cell. Jan 19 2010;17(1):77-88.