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Article

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

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The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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Center of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia
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Bioinformatics Core Facility, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
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The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
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Department of Otolaryngology—Head and Neck Surgery, Soroka University Medical Center, Beer-Sheva 84105, Israel
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Department of Otorhinolaryngology and Head & Neck Surgery, Barzilay Medical Center, Ashkelon 7830604, Israel
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School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China
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Department of Otolaryngology—Head and Neck Surgery, University of California San Francisco, San Francisco, CA 94143, USA
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Department of Life Sciences, Faculty of Life Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
*
Authors to whom correspondence should be addressed.
Academic Editor: Miriam Martini
Cancers 2021, 13(9), 2250; https://doi.org/10.3390/cancers13092250
Received: 25 March 2021 / Revised: 27 April 2021 / Accepted: 29 April 2021 / Published: 7 May 2021
(This article belongs to the Special Issue Targeting PI3K Signaling in Cancer)
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.
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+. View Full-Text
Keywords: head and neck cancer; HPV; IGF2; IGF1R; PI3K; therapy resistance; drug combinations head and neck cancer; HPV; IGF2; IGF1R; PI3K; therapy resistance; drug combinations
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MDPI and ACS Style

Badarni, M.; Prasad, M.; Golden, A.; Bhattacharya, B.; Levin, L.; Yegodayev, K.M.; Dimitstein, O.; Joshua, B.-Z.; Cohen, L.; Khrameeva, E.; Kong, D.; Porgador, A.; Braiman, A.; Grandis, J.R.; Rotblat, B.; Elkabets, M. IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer. Cancers 2021, 13, 2250. https://doi.org/10.3390/cancers13092250

AMA Style

Badarni M, Prasad M, Golden A, Bhattacharya B, Levin L, Yegodayev KM, Dimitstein O, Joshua B-Z, Cohen L, Khrameeva E, Kong D, Porgador A, Braiman A, Grandis JR, Rotblat B, Elkabets M. IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer. Cancers. 2021; 13(9):2250. https://doi.org/10.3390/cancers13092250

Chicago/Turabian Style

Badarni, Mai, Manu Prasad, Artemiy Golden, Baisali Bhattacharya, Liron Levin, Ksenia M. Yegodayev, Orr Dimitstein, Ben-Zion Joshua, Limor Cohen, Ekaterina Khrameeva, Dexin Kong, Angel Porgador, Alex Braiman, Jennifer R. Grandis, Barak Rotblat, and Moshe Elkabets. 2021. "IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer" Cancers 13, no. 9: 2250. https://doi.org/10.3390/cancers13092250

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