Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma

Abstract

Undifferentiated pleomorphic sarcomas (UPSs) are aggressive mesenchymal malignancies with no definitive cell of origin or specific recurrent genetic hallmarks. These tumors are largely chemoresistant; thus, identification of potential therapeutic targets is necessary to improve patient outcome. Previous studies demonstrated that high expression of activated protein kinase B (AKT) in patients with UPS corresponds to poor disease-specific survival. Here, we demonstrate that inhibiting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling using a small molecule inhibitor reduced UPS cell proliferation and motility and xenograft growth; however, increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) indicated the potential for adaptive resistance following treatment through compensatory receptor activation. Co-treatment with a dual PI3K/mTOR inhibitor and an anti-IGF1R kinase inhibitor reduced in vivo tumor growth rates despite a lack of antiproliferative effects in vitro. Moreover, this combination treatment significantly decreased UPS cell migration and invasion, which is linked to changes in p27 subcellular localization. Our results demonstrate that targeted inhibition of multiple components of the IGF1R/PI3K/mTOR pathway was more efficacious than single-agent therapy and suggest that co-targeting this pathway could be a beneficial therapeutic strategy for patients with UPS.

The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

“…This effect was accompanied with a partial and durable inhibition of phospho‐S6 and a transient inhibition of phospho‐AKT (S473) which recovered pretreatment levels after 24 hr. Several mechanisms of resistance involving the recovering of PI3K/AKT signaling after the activation of mTORC2 via IGFR1 or PDGFR signaling have been described for different mTOR inhibitors . Therefore, the restoring of AKT signaling may be in the basis of the resistance to the treatment with EC‐70124.…”

“…Several mechanisms of resistance involving the recovering of PI3K/AKT signaling after the activation of mTORC2 via IGFR1 or PDGFR signaling have been described for different mTOR inhibitors. 20,22,23 Therefore, the restoring of AKT signaling may be in the basis of the resistance to the treatment with EC-70124. Nevertheless, we have not detected an increased phosphorilation of IGF1R or PDGFR after EC-70124-treatment in vitro (Supporting Information Fig.…”

“…This limited response may be explained by the fact that these compounds are efficient inhibitors of mTORC1 but not mTORC2 which contribute to induce an adaptive resistance due to the reactivation of AKT . Therefore, a new generation of inhibitors able to target both complexes and/or combinatorial strategies aimed to prevent resistance to mTOR inhibitors are being tested in sarcomas …”

“…22 Therefore, a new generation of inhibitors able to target both complexes and/or combinatorial strategies aimed to prevent resistance to mTOR inhibitors are being tested in sarcomas. [22][23][24] Targeting several key oncogenic signals with a single agent may constitute an ideal alternative to increase efficiency and prevent the activation of resistance mechanisms. In line with this aim, EC-70124 is a hybrid indolocarbazole analog 25 with a potent multikinase inhibitor spectrum affecting key signaling kinases implicated in pro-survival and proliferative pathways.…”

Neurotensin receptor 1 is a new therapeutic target for human undifferentiated pleomorphic sarcoma growth

“…The clinical benefit of chemotherapy and radiation remains unclear. Recently, genetic studies have contributed to an increased understanding of sarcomas and provided possible therapeutic targets . In this study, we investigated NTSR1 as a target for anti‐UPS therapy using the NTSR1 inhibitor in vitro and in vivo.…”