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

Mai Badarni; 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; Moshe Elkabets

doi:10.3390/cancers13092250

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

Cancers (Basel). 2021 May 7;13(9):2250. doi: 10.3390/cancers13092250.

Authors

Mai Badarni^{1

2}, Manu Prasad^{1

2}, Artemiy Golden³, Baisali Bhattacharya^{1

2}, Liron Levin^{4

5}, Ksenia M Yegodayev^{1

2}, Orr Dimitstein^{2

6}, Ben-Zion Joshua^{2

7}, Limor Cohen^{1

2}, Ekaterina Khrameeva³, Dexin Kong⁸, Angel Porgador^{1

2}, Alex Braiman^{1

2}, Jennifer R Grandis⁹, Barak Rotblat^{5

10}, Moshe Elkabets^{1

2}

Affiliations

¹ The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
² Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
³ Center of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia.
⁴ Bioinformatics Core Facility, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
⁵ The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
⁶ Department of Otolaryngology-Head and Neck Surgery, Soroka University Medical Center, Beer-Sheva 84105, Israel.
⁷ Department of Otorhinolaryngology and Head & Neck Surgery, Barzilay Medical Center, Ashkelon 7830604, Israel.
⁸ School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.
⁹ Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
¹⁰ Department of Life Sciences, Faculty of Life Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.

Abstract

Over 50% of human papilloma positive head-and-neck cancer (HNC^HPV+) 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 HNC^HPV+ 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 HNC^HPV+ 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 HNC^HPV+ 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 HNC^HPV+.

Keywords: HPV; IGF1R; IGF2; PI3K; drug combinations; head and neck cancer; therapy resistance.

Abstract

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