Abstract A29: Targeting the EGFR in high-grade glioma

Abstract

The epidermal growth factor receptor (EGFR) is altered in 57% of high grade glioma (HGG) by mutation, rearrangement and/or focal amplification, suggesting it should be a target for therapy. However, attempts to therapeutically target EGFR in HGG patients have failed for reasons that remain largely unknown. We have derived a panel of primary cell lines from HGG patients expressing different forms of the EGFR including the most common mutations: the autoactivating deletion EGFRvIII and the extracellular domain point mutation A289V. Using anti-proliferative assays and cell cycle analysis we screened our HGG cell lines for response to Panitumumab (an EGFR targeting antibody) or Dacomitinib (an irreversible TKI targeting EGFR). The anti-proliferative activity of Panitumumab and Dacomitinib showed a similar profile across the HGG cell lines, but the response to EGFR inhibition ranged from resistant to highly sensitive. In order to improve the anti-tumour response to Panitumumab we tested it in combination with either a MEK inhibitor (Trametinib) or a PI3K inhibitor (BYL719), as both signalling pathways are downstream of EGFR. The combination of Panitumumab and Trametinib showed additive anti-tumour activity against HGG cell lines expressing the wtEGFR, whereas the combination of Panitumumab with BYL719 did not display additivity. In contrast, EGFRvIII cell lines showed an additive anti-tumour response to Panitumumab and BYL719 but not Trametinib. More generally, the activation of the ras/MEK/ERK pathway through either ras mutation or integrin engagement mediated resistance to EGFR-targeted therapeutics. Finally, the SB2 HGG cell line, which contains the A289V mutation, was completely resistant to EGFR therapy due to an activating mutation in PI3KCA. We are currently confirming these in vitro observations in orthotopic xenograft models. The epidermal growth factor receptor (EGFR) is altered in 57% of high grade glioma (HGG) by mutation, rearrangement and/or focal amplification, suggesting it should be a target for therapy. However, attempts to therapeutically target EGFR in HGG patients have failed for reasons that remain largely unknown. We have derived a panel of primary cell lines from HGG patients expressing different forms of the EGFR including the most common mutations: the autoactivating deletion EGFRvIII and the extracellular domain point mutation A289V. Using anti-proliferative assays and cell cycle analysis we screened our HGG cell lines for response to Panitumumab (an EGFR targeting antibody) or Dacomitinib (an irreversible TKI targeting EGFR). The anti-proliferative activity of Panitumumab and Dacomitinib showed a similar profile across the HGG cell lines, but the response to EGFR inhibition ranged from resistant to highly sensitive. In order to improve the anti-tumour response to Panitumumab we tested it in combination with either a MEK inhibitor (Trametinib) or a PI3K inhibitor (BYL719), as both signalling pathways are downstream of EGFR. The combination of Panitumumab and Trametinib showed additive anti-tumour activity against HGG cell lines expressing the wtEGFR, whereas the combination of Panitumumab with BYL719 did not display additivity. In contrast, EGFRvIII cell lines showed an additive anti-tumour response to Panitumumab and BYL719 but not Trametinib. More generally, the activation of the ras/MEK/ERK pathway through either ras mutation or integrin engagement mediated resistance to EGFR-targeted therapeutics. Finally, the SB2 HGG cell line, which contains the A289V mutation, was completely resistant to EGFR therapy due to an activating mutation in PI3KCA. We are currently confirming these in vitro observations in orthotopic xenograft models. This work is providing new insights into the mechanism that control response to EGFR-targeted therapeutics and should lead to therapeutic combinations that have efficacy in HGG patients. Note: This abstract was not presented at the conference. Citation Format: Vino Pillay, Sameer Greenall, Terrance G. Johns. Targeting the EGFR in high-grade glioma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A29.