Inhibition of Tumor Growth by Targeted Anti-EGFR/IGF-1R Nanobullets Depends on Efficient Blocking of Cell Survival Pathways

Abstract

The clinical efficacy of epidermal growth factor receptor (EGFR)-targeted inhibitors is limited due to resistance mechanisms of the tumor such as activation of compensatory pathways. Crosstalk between EGFR and insulin-like growth factor 1 (IGF-1R) signaling has been frequently described to be involved in tumor proliferation and resistance. One of the attractive features of nanomedicines is the possibility to codeliver agents that inhibit different molecular targets in one nanocarrier system, thereby strengthening the antitumor effects of the individual agents. Additionally, exposure to healthy tissues and related unwanted side-effects can be reduced. To this end, we have recently developed anti-EGFR nanobody (Nb)-liposomes loaded with the anti-IGF-1R kinase inhibitor AG538, which showed promising antiproliferative effects in vitro. In the present study, we have further evaluated the potential of this dual-active nanomedicine in vitro and for the first time in vivo. As intended, the nanomedicine inhibited EGFR and IGF-1R signaling and subsequent activation of downstream cell proliferation and survival pathways. The degree of inhibition induced by the nanomedicine on a molecular level correlated with cytotoxicity in tumor cell proliferation assays and may even be predictive of the response to nanomedicine treatment in tumor xenograft models. Combination therapy with kinase inhibitor-loaded Nb-liposomes is therefore an appealing strategy for inhibiting the proliferation of tumors that are highly dependent on EGFR and IGF-1R signaling.

Amphiregulin promotes the immunosuppressive activity of intrahepatic CD4+ regulatory T cells to impair CD8+ T‐cell immunity against hepatitis B virus infection

“…35 The relationship between EGFR and cancer has been elucidated in previous research. 36,37 However, its role in regulating T-cell functions has not been addressed. Actually, little information about the expression of EGFR on T cells has been generated until recently, suggesting that under most conditions EGFR might not be expressed on T cells.…”

The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link

“…Promising data have emerged from in vitro and in vivo pre-clinical investigations regarding anti-EGFR/IGF-IR inhibitor “nanobullets,” EGFR nanobody liposomes loaded with the IGF-IR inhibitor AG538. This therapy may aid specificity, but would also benefit from stratification of patients through predictive biomarkers ( 155 ).…”

Both epidermal growth factor and insulin-like growth factor receptors are dispensable for structural intestinal adaptation

“…These structural homologous receptors are recognized for tumor cell regulation of proliferation, survival, apoptosis, and angiogenesis [28, 29] making these two receptors favorable targets for cancer therapy [24, 29, 30]. Recent studies have shown IGF1R mainly mediates via the PI3K/AKT pathway while the EGFR mediates through the Ras/MAP kinase pathway [31, 32].…”

“…Recent studies have shown IGF1R mainly mediates via the PI3K/AKT pathway while the EGFR mediates through the Ras/MAP kinase pathway [31, 32]. Multiple studies have shown selective inhibition of one receptor will lead to compensatory and enhanced activation of the other receptor axis [29, 33, 34]. These cellular and molecular mechanistic observations have led to research on specific targeted therapy for dual inhibition of EGFR and IGF1R [28–30, 35].…”