Tumor-Specific Regulation Of Receptor Tyrosine Kinases By Grp94

The Endoplasmic Reticulum (ER) HSP90 paralog, Glucose Regulated Protein 94 (Grp94) is a molecular chaperone often overexpressed in tumors. Clinically, expression of Grp94 correlates with advanced stage and poor survival in a variety of cancers, and is closely linked to cancer growth and metastasis. The majority of the cancer-related studies on Grp94 have focused narrowly on the immunogenic activity of Grp94/peptide complexes and the involvement of this protein in the secretion of IGF-I and IGF-II and the regulation of Toll-like receptors and integrins. Recently however, novel mechanistic understanding emerged regarding the cancer specific roles of Grp94: the important and unexpected tumor specific translocation of Grp94 from ER to plasma membrane to regulate the altered expression and function of plasma membrane associated cancer-proteins and its role in sustaining their transforming ability. In this respect, we found that the high density HER2 formations at the plasma membrane of HER2-overexpressing breast cancer cells necessitate Grp94 (Nat Chem Biol 2013 9(11):677-84). Inhibition of Grp94 in these cells was sufficient to destabilize plasma membrane HER2, inhibit its signaling properties, target HER2 towards a degradative pathway and as a result kill the cancer cell. We here use a chemical biology approach combined with classical methods to produce preliminary evidence for an unanticipated oncogenic role for Grp94 in maintaining high density receptor tyrosine kinases (RTKs) at the plasma membrane, particularly in cancer cells where RTKs are required to channel an amplified signaling. Our data indicate that under conditions in which stress is imposed on the cell by proteome alterations (i.e. RTK overexpression), the chaperoning function of Grp94 is vital for proper functioning of RTKs. In these cells Grp94 translocates to the plasma membrane where it functions to maintain an active conformation of RTKs and to stabilize downstream signaling through the receptor. In contrast, we find no effect of Grp94 inhibition in cells with normal or physiological RTK function/expression. Our findings provide a strong rationale for the use of chemical tools in the investigation of Grp94 associated oncogenic mechanisms and support the development of Grp94 inhibitors as a novel targeted therapy for the treatment of cancers dependent on increased signaling through plasma membrane RTKs, many of which tend to have an aggressive presentation. Citation Format: Pengrong Yan, Hardik Patel, Pallav Patel, Stefan Ochiana, Weilin Sun, Smit Shah, Paola Finotti, Cynthia Leifer, Zihai Li, Daniel Gewirth, Tony Taldone, Gabriela Chiosis. Tumor-specific regulation of receptor tyrosine kinases by Grp94. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4716. doi:10.1158/1538-7445.AM2015-4716