Abstract
In many cancers, combination therapy regimens are successfully improving response and survival rates, but the challenges of toxicity remain. GRP78, the master regulator of the unfolded protein response, is emerging as a target that is upregulated in tumors, specifically following treatment, and one that impacts tumor cell survival and disease recurrence. Here, we show IT-139, an antitumor small molecule inhibitor, suppresses induction of GRP78 from different types of endoplasmic reticulum (ER) stress in a variety of cancer cell lines, including those that have acquired therapeutic resistance, but not in the non-cancer cells being tested. We further determined that IT-139 treatment exacerbates ER stress while at the same time suppresses GRP78 induction at the transcriptional level. Our studies revealed a differential effect of IT-139 on chaperone protein family expression at multiple levels in different cancer cell lines. In xenograft studies, IT-139 decreased BRAF inhibitor upregulation of GRP78 expression in the tumor, while having minimal effect on GRP78 expression in the adjacent normal cells. The preferential decrease in GRP78 levels in tumor cells over normal cells, supported by the manageable safety profile seen in the Phase 1 clinical trial, reinforce the value IT-139 brings to combination therapies as it continues its clinical development.
Highlights
An emerging target that plays a critical role in tumor cell survival, tumor progression, and drug resistance is the 78-kDa glucose-regulated protein (GRP78), known as the immunoglobulin binding protein (BiP) and heat shock protein A5 (HSPA5) [1]
Cytotoxicity in these studies is defined as the maximal concentration that inhibits the viability of cells by 50% (IC50), or the half-maximal effective concentration (EC50) that induces a response compared to untreated control cells at 72 hrs
GRP78 is highly expressed in a wide variety of cancers and controls multiple steps of tumorigenesis in response to environmental and therapeutic insult
Summary
An emerging target that plays a critical role in tumor cell survival, tumor progression, and drug resistance is the 78-kDa glucose-regulated protein (GRP78), known as the immunoglobulin binding protein (BiP) and heat shock protein A5 (HSPA5) [1]. In non-stressed normal cells GRP78 resides in the endoplasmic reticulum (ER) where it regulates the integrity of the ER and the correct folding of newly synthesized proteins [2]. It functions by binding Ca2+ to maintain metabolic homeostasis and facilitates the export of misfolded proteins for degradation. As GRP78 is titrated away from ATF6, PERK, and IRE1, the unfolded protein response (UPR) is initiated. The UPR, along with other major mechanisms that include translation attenuation, increased expression of ER chaperones, enhanced ERassociated protein degradation and apoptosis, represents an evolutionarily conserved adaptive response that allows cells to overcome proteotoxic stress [4, 5]. The UPR is an important survival pathway utilized by cancer cells
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