Significant effect of anti-tyrosine kinase inhibitor (Gefitinib) on overall survival of the glioblastoma multiforme patients in the backdrop of mutational status of epidermal growth factor receptor and PTEN Genes

Abstract

Introduction:We aimed to assess the effect of anti-tyrosine kinase inhibitors (TKIs) (gefitinib) in overall survival (OS) of the glioblastoma multiforme (GBM) patients in the backdrop of mutational status of epidermal growth factor receptor (EGFR) and PTEN genes.Materials and Methods:All the patients subjected to resection or biopsies were put on gefitinib, and radiotherapy was delivered as per the hospital protocol. EGFR and PTEN mutational spectrum was performed by single-strand conformation polymorphism followed by DNA sequencing.Results:In total, 50% GBM tumors had mutation either in EGFR or PTEN. Median progression-free survival (PFS) and OS observed in patients with EGFR +ve/PTEN −ve were significantly favorable (P < 0.05) which aggregated to 9(7, 11) months and 20 (16, 24) months, respectively, than 6 (4, 8) months and 13 (7, 19) months in patients with PTEN +ve/EGFR −ve. Patients positive for both EGFR/PTEN had lower disease-free survival and OS of 6 and 9 months as compared to 6 (5, 7) and 14 (12, 24) months for those negative for both EGFR/PTEN.Conclusions:We conclude that EGFR gene alterations with wild-type PTEN are associated with significantly better PFS and OS in patients treated with anti-TKIs (gefitinib). Combined EGFR and PTEN gene mutation is associated with significantly poor response to gefitinib in terms of median OS.

A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity

“…We next explored more targeted drug treatments for specific signaling pathways based on somatic mutations identified in parental tumors from a routinely performed clinical sequencing panel ( Figure 6D; Table S1). EGFR tyrosine kinase inhibition did not improve the overall survival of patients with glioblastomas (Rich et al, 2004;Uhm et al, 2011), but showed a survival benefit in patients with mutated EGFR in the absence of downstream PTEN mutation (Arif et al, 2018;Mellinghoff et al, 2005). We hypothesized that the clinical benefit could be mutation-specific.…”

Receptor Tyrosine Kinase Signaling and Targeting in Glioblastoma Multiforme

“…First-generation reversible small-molecule inhibitors, Erlotinib and Gefitinib, which have been shown to be effective in treating non-small cell lung cancer [ 253 ], have also been extensively researched as therapeutic options for GBM [ 254 ]. In fact, early preclinical studies of Erlotinib and Gefitinib presented promising results when tested against GBM cell lines [ 255 , 256 ], but subsequent clinical studies of these ATP-competitive small molecules as monotherapeutic agents [ 257 ] or in combination therapy [ 258 , 259 ] were disappointing. Of note, Erlotinib is highly effective in inhibiting EGFR with kinase domain mutations that are prevalent in lung cancer [ 260 ] as opposed to its low efficacy in blocking EGFR with extracellular domain mutations that are characteristic of GBM [ 261 , 262 ].…”

Cinobufagin Is a Selective Anti-Cancer Agent against Tumors with EGFR Amplification and PTEN Deletion

“…GBM still remains a challenge because these tumors are resistant to anti-EGFR therapy, always relapse ( Stupp et al, 2009 ) and recurrent tumors are less sensitive to chemotherapy than the primary tumor, developing novel anti-EGFR agents remains urgent ( Campos et al, 2016 ; Eskilsson et al, 2018 ). Almost half of the patients carry EGFR-driven tumor with phosphatase and tensin homolog (PTEN) deletion, which are resistant to EGFR target therapy, implying PTEN deficiency plays an important role in resistance to anti-EGFR therapy ( Mellinghoff et al, 2007 ; Arif et al, 2018 ; Brito et al, 2019 ). Using PTEN-deficient glioblastoma cell line U87MG-EGFRvIII screening and U87MG-PTEN counter-screening, we have previously reported that G5-7 selectively blocked Janus kinase 2 (Jak2), preventing GBM proliferation ( He et al, 2013 ).…”