The synergistic inhibitory effect of combining therapies targeting EGFR and mitochondria in sarcomas

Abstract

Our group previously demonstrated that sarcoma cell lines were insensitive to epidermal growth factor receptor (EGFR) inhibitor gefitinib monotherapy. PENAO, an anti-tumour metabolic compound created in our laboratory, is currently in clinical trials. Considering the positive regulation of tumour energy production by both the EGFR signalling and tumour metabolism pathways, this study aimed to investigate the effect and mechanisms of combination therapy using gefitinib and PENAO in sarcoma cell lines in vitro and in vivo. PENAO monotherapy reduced proliferation in 12 sarcoma cell lines. Combining gefitinib and PENAO resulted in synergistic inhibition in both a time-and dosedependent manner in 3 sarcoma cell lines with less prominent monotherapy effects. Combined treatment significantly enhanced cell death and perturbed mitochondrial function. In vivo combination therapy with PENAO and gefitinib was non-toxic to mice and significantly delayed tumour growth and prolonged survival. At 20 days after treatment, tumours from the combination treated mice were significantly smaller than those from untreated and single drug treated mice. The survival curves also showed significant difference across and between groups. The combination of PENAO and gefitinib in vitro and in vivo, shows promise as a treatment pathway in this poor outcome tumour.

Nanodelivery Systems Targeting Epidermal Growth Factor Receptors for Glioma Management

“…A comprehensively studied downstream pathway of EGFR is the PI3K/AKT/mTOR, which is critically involved in regulating cell apoptosis, autophagy, proliferation, and metabolism. Dysregulation of the pathway, as mentioned earlier, played a prominent role in various cancers [ 92 , 93 ]. Therapeutic strategies targeting PI3K/AKT in GBM have given promising results in the in vitro and in vivo xenograft models; however, clinical safety and efficacy need to be proven.…”

“…The therapeutic efficacy was minimal or nil in the case of first and second-generation EGFR inhibitors for the treatment of recurrent GBM [ 109 , 110 ]. The primary reasons for the above drugs’ failure were their inability to cross the BBB and the requirement of a relatively high amount of drug concentrations in the brain [ 92 ], which in turn limited their usage. By overcoming the above-said limitations, effective therapy for GBM could be discovered [ 92 ].…”

“…The primary reasons for the above drugs’ failure were their inability to cross the BBB and the requirement of a relatively high amount of drug concentrations in the brain [ 92 ], which in turn limited their usage. By overcoming the above-said limitations, effective therapy for GBM could be discovered [ 92 ].…”

Potential for Using EGFR Expression in Rhabdomyosarcoma, Osteosarcoma and Ewing’s Sarcoma: Clinicopathological and Prognostic Significance

“…Cancer cells are dependent on mitochondrial metabolism for glucose generation due to their high energetic requirements. These enzymes act in conjunction with the growth factors MAPK, PI3K/Akt, and JAK/STAT, which block cell death (Wang et al, 2020). Inactivation of signaling in several downstream EGFR pathways such as PI3K/AKT and JAK/STAT3 has also been incriminated in osteosarcoma progression and metastasis (Yang et al, 2021).…”