Tumor Cell Autonomous RON Receptor Expression Promotes Prostate Cancer Growth Under Conditions of Androgen Deprivation

Abstract

Current treatment strategies provide minimal results for patients with castration-resistant prostate cancer (CRPC). Attempts to target the androgen receptor have shown promise, but resistance ultimately develops, often due to androgen receptor reactivation. Understanding mechanisms of resistance, including androgen receptor reactivation, is crucial for development of more efficacious CRPC therapies. Here, we report that the RON receptor tyrosine kinase is highly expressed in the majority of human hormone-refractory prostate cancers. Further, we show that exogenous expression of RON in human and murine prostate cancer cells circumvents sensitivity to androgen deprivation and promotes prostate cancer cell growth in both in vivo and in vitro settings. Conversely, RON loss induces sensitivity of CRPC cells to androgen deprivation. Mechanistically, we demonstrate that RON overexpression leads to activation of multiple oncogenic transcription factors (namely, β-catenin and NF-κB), which are sufficient to drive androgen receptor nuclear localization and activation of AR responsive genes under conditions of androgen deprivation and support castration-resistant growth. In total, this study demonstrates the functional significance of RON during prostate cancer progression and provides a strong rationale for targeting RON signaling in prostate cancer as a means to limit resistance to androgen deprivation therapy.

MST1R (RON) expression is a novel prognostic biomarker for metastatic progression in breast cancer patients

“…Whereas established biomarkers in BC strongly indicate a predictive response to therapeutics targeting the biomarker itself (hormone therapies targeting ER/PR and trastuzumab/pertuzumab targeting HER2), the predictive capacity of MST1R expression for MST1R-targeted therapeutics has not yet been investigated. Currently, there are no FDAapproved inhibitors for MST1R on the market; however, a Phase I trial has been completed on the BMS777607 (formerly ASLAN002) compound showing promising results on MST1R-mediated effects in preclinical models of breast and prostate cancers [14,25]. Based on our findings, a prospective study to ascertain the predictive potential of MST1R protein expression on response to BMS777607 should be encompassed in the scientific aims of a future Phase II trial.…”

“…Slides were stained in a blinded fashion with an established MST1R staining protocol using a polyclonal anti-MST1R β-chain antibody (Santa Cruz, C-20 clone, Lot#B2316) [16,23,29]. Scoring occurred in a blinded fashion by a single individual (that did not perform the staining procedure) using a tissue positivity score (0-100) and intensity score (0-3) that were multiplied together to obtain a histology score (H-Score; 0-300) [14,16,31,32]. A total of 186 samples were used for analyses.…”

“…The MST1R (also known as RON) receptor tyrosine kinase (RTK) is a member of the c-Met family of RTKs that is expressed in epithelial cells and terminally-differentiated macrophages [8][9][10][11][12]. MST1R is overexpressed in numerous solid tumors including breast, prostate, pancreas, and more with strong oncogenic function elicited through various signaling mechanisms [8][9][10][13][14][15][16][17][18][19][20][21]. MST1R overexpression incidence and examination of its prognostic features with respect to survival and metastatic progression in BC have been reported, but are limited by subtype, sample size, technology, access to clinical information, or are limited to node-negative samples lacking overall survival data [8,12,[21][22][23][24].…”

Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

“…6 Recently, increased RON expression has also been documented in bladder and prostate cancers. [12][13][14][15] These findings help identify tumors for focused analysis of RON pathogenesis. In breast cancer, RON is known to be expressed in more than 80% of samples with overexpression in ~36% of cases.…”

“…9 Since then, increased RON expression has been documented in various types of cancer including those from colorectal, lung, breast, pancreatic, and others. [6][7][8][9][10][11][12][13] A systematic analysis using tumor tissue microarrays demonstrates that RON overexpression at the rate of 30% and above occurs in tumors including colorectal, breast, and pancreatic cancers. 6 Recently, increased RON expression has also been documented in bladder and prostate cancers.…”