IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer
| العنوان: | IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer |
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| المؤلفون: | Liron Levin, Jennifer R. Grandis, Moshe Elkabets, Orr Dimitstein, Alex Braiman, Manu Prasad, Ben-Zion Joshua, Ekaterina Khrameeva, Limor Cohen, Angel Porgador, Mai Badarni, Baisali Bhattacharya, Artemiy Golden, Ksenia M. Yegodayev, Dexin Kong, Barak Rotblat |
| المصدر: | Cancers Volume 13 Issue 9 Cancers, vol 13, iss 9 Cancers, Vol 13, Iss 2250, p 2250 (2021) |
| بيانات النشر: | MDPI, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, HPV, drug combinations, therapy resistance, Oncology and Carcinogenesis, PI3K, Article, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Downregulation and upregulation, In vivo, IGF1R, medicine, Dental/Oral and Craniofacial Disease, RC254-282, PI3K/AKT/mTOR pathway, Cancer, Insulin-like growth factor 1 receptor, Chemistry, Cell growth, IGF2, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 030104 developmental biology, Oncology, 5.1 Pharmaceuticals, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Sexually Transmitted Infections, head and neck cancer, Development of treatments and therapeutic interventions, Ex vivo |
| الوصف: | Simple Summary In the current study, we delineate the molecular mechanisms of acquisition of resistance to two isoform-selective inhibitors of PI3K (isiPI3K), alpelisib and taselisib, in human papillomavirus positive head and neck cell lines. By comparing RNA sequencing of isiPI3K-sensitive tumor cells and their corresponding isiPI3K-acquired-resistant tumor cells, we found that overexpression of insulin growth factor 2 (IGF2) is associated with the resistance phenotype. We further demonstrated by gain and loss of function studies that IGF2 plays a causative role in limiting the sensitivity of human papillomavirus-positive head and neck cell lines. Moreover, we show that blocking IGF2 stimulation activity, using an inhibitor of the IGF1 receptor (IGF1R), enhances isiPI3K efficacy and displays a synergistic anti-tumor effect in vitro and superior anti-tumor activity ex vivo and in vivo. 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+. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2072-6694 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::60ae3a9e9ae2da39af8d2764c25a624e http://europepmc.org/articles/PMC8125641 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....60ae3a9e9ae2da39af8d2764c25a624e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20726694 |
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