IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer

Abstract

Over 50% of human papilloma positive head-and-neck cancer (HNCHPV+) patients harbor genomic-alterations in PIK3CA, leading to hyperactivation of the phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) pathway. Nevertheless, despite PI3K pathway activation in HNCHPV+ tumors, the anti-tumor activities of PI3K pathway inhibitors are moderate, mostly due to the emergence of resistance. Thus, for potent and long-term tumor management, drugs blocking resistance mechanisms should be combined with PI3K inhibitors. Here, we delineate the molecular mechanisms of the acquisition of resistance to two isoform-selective inhibitors of PI3K (isiPI3K), alpelisib (BYL719) and taselisib (GDC0032), in HNCHPV+ cell lines. By comparing the transcriptional landscape of isiPI3K-sensitive tumor cells with that of their corresponding isiPI3K-acquired-resistant tumor cells, we found upregulation of insulin growth factor 2 (IGF2) in the resistant cells. Mechanistically, we show that upon isiPI3K treatment, isiPI3K-sensitive tumor cells upregulate the expression of IGF2 to induce cell proliferation via the activation of the IGF1 receptor (IGF1R). Stimulating tumor cells with recombinant IGF2 limited isiPI3K efficacy and released treated cells from S phase arrest. Knocking-down IGF2 with siRNA, or blocking IGF1R with AEW541, resulted in superior anti-tumor activity of isiPI3K in vitro and ex vivo. In vivo, the combination of isiPI3K and IGF1R inhibitor induced stable disease in mice bearing either tumors generated by the HNCHPV+ UM-SCC47 cell line or HPV+ patient-derived xenografts. These findings indicate that IGF2 and the IGF2/IGF1R pathway may constitute new targets for combination therapies to enhance the efficacy of PI3K inhibitors for the treatment of HNCHPV+.

Manipulating the tumor immune microenvironment to improve cancer immunotherapy: IGF1R, a promising target

“…All these PI3K isoforms promote tumor cell survival, proliferation and metastasis by regulating different processes including tumor cell metabolism, angiogenesis and by modulating the TME and immunity, mainly via the activation of the AKT/mTOR and the GSK3β/beta-catenin pathways ( 11 ) ( Figure 1 ). Resistance to PI3K inhibition in cancer cells occurs via activation of different compensatory mechanisms ( 12 ) or adaptive responses, including the activation of the IGF1R pathway ( 12 – 14 ). For instance, resistance to PI3K delta inhibition in a chronic model of lymphocytic leukemia is linked to the upregulation of the IGF1R expression resulting in an enhancement of the MAPK pathway ( 15 ).…”

LINC01132 and LINC02542 modulate the PIK3/ACT signaling pathway in breast cancer patients through regulation of IGF2: a systems biology-based biomarker discovery

“…As mentioned, overexpression of IGF2 can lead to resistance to targeted cures, such as EGFR inhibitors, by reactivating the AKT and MAPK pathways in lung cancer and cholangiocarcinoma [53]. Indicating that the IGF axis performs a role in keeping survival signaling pathways and reducing the effectiveness of PI3K and AKT inhibitors [54].…”

Developing a dual VEGF/PDL1 inhibitor based on high-affinity scFv heterodimers as an anti-cancer therapeutic strategy

“…HEK 293-T cells [American Type Culture Collection (ATCC), Manassas, VA, USA] and head and neck SCC47 38 cells (kindly supplied by Reidar Grénman, Department of Otorhinolaryngology—Head & Neck Surgery, Turku University, Finland) were grown in Dulbecco’s modified Eagle’s medium (Biological Industries, Beit Haemek, Israel). Glioblastoma U87MG cells (ATCC) were grown in MEM medium (Biological Industries).…”