Therapeutic Destruction of Insulin Receptor Substrates for Cancer Treatment

Overview

Journal Cancer Res

Specialty Oncology

Date 2013 May 9

PMID 23651636

Citations 72

Authors

Hadas Reuveni

Efrat Flashner-Abramson

Lilach Steiner

Kirill Makedonski

Renduo Song

Alexei Shir

Meenhard Herlyn

Menashe Bar-Eli

Alexander Levitzki

Affiliations

Soon will be listed here.

Abstract

Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and antiapoptotic signaling from insulin-like growth factor 1 receptor (IGF-IR), insulin receptor (IR), and other oncoproteins. IRS1 plays a central role in cancer cell proliferation, its expression is increased in many human malignancies, and its upregulation mediates resistance to anticancer drugs. IRS2 is associated with cancer cell motility and metastasis. Currently, there are no anticancer agents that target IRS1/2. We present new IGF-IR/IRS-targeted agents (NT compounds) that promote inhibitory Ser-phosphorylation and degradation of IRS1 and IRS2. Elimination of IRS1/2 results in long-term inhibition of IRS1/2-mediated signaling. The therapeutic significance of this inhibition in cancer cells was shown while unraveling a novel mechanism of resistance to B-RAF(V600E/K) inhibitors. We found that IRS1 is upregulated in PLX4032-resistant melanoma cells and in cell lines derived from patients whose tumors developed PLX4032 resistance. In both settings, NT compounds led to the elimination of IRS proteins and evoked cell death. Treatment with NT compounds in vivo significantly inhibited the growth of PLX4032-resistant tumors and displayed potent antitumor effects in ovarian and prostate cancers. Our findings offer preclinical proof-of-concept for IRS1/2 inhibitors as cancer therapeutics including PLX4032-resistant melanoma. By the elimination of IRS proteins, such agents should prevent acquisition of resistance to mutated-B-RAF inhibitors and possibly restore drug sensitivity in resistant tumors.

Citing Articles

NT157 exhibits antineoplastic effects by targeting IRS and STAT3/5 signaling in multiple myeloma.

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PMID: 38523043 PMC: 11726112. DOI: 10.1016/j.htct.2024.02.017.

Inhibition of LAR attenuates neuroinflammation through RhoA/IRS-1/Akt signaling pathway after intracerebral hemorrhage in mice.

Le C, Hu X, Tong L, Ye X, Zhang J, Yan J J Cereb Blood Flow Metab. 2023; 43(6):869-881.

PMID: 36802818 PMC: 10196755. DOI: 10.1177/0271678X231159352.

Suppression of Insulin Receptor Substrate 1 Inhibits Breast Cancer Growth In Vitro and in Female Athymic Mice.

Zhang X, Varma S, Yee D Endocrinology. 2023; 164(3).

PMID: 36610717 PMC: 10091499. DOI: 10.1210/endocr/bqac214.

Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth.

Chattopadhyay C, Bhattacharya R, Roszik J, Khan F, Wells G, Villanueva H Cancers (Basel). 2022; 14(24).

PMID: 36551732 PMC: 9777326. DOI: 10.3390/cancers14246247.

Case report: Unique FLT4 variants associated with differential response to anlotinib in angiosarcoma.

Gu Y, Meng J, Ju Y, You X, Sun T, Lu J Front Oncol. 2022; 12:1027696.

PMID: 36452496 PMC: 9702819. DOI: 10.3389/fonc.2022.1027696.

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