AbstractMetastatic cutaneous melanoma is a fatal skin cancer. Resistance to targeted and immune therapies limits the benefits of current treatments. Identifying and adding anti‐resistance agents to current treatment protocols can potentially improve clinical responses. Myocardin‐related transcription factor (MRTF) is a transcriptional coactivator whose activity is indirectly regulated by actin and the Rho family of GTPases. We previously demonstrated that development of BRAF inhibitor (BRAFi) resistance frequently activates the Rho/MRTF pathway in human and mouse BRAFV600E melanomas. In clinical trials, pretreatment with BRAFi reduces the benefit of immune therapies. We aimed to test the efficacy of concurrent treatment with our MRTF pathway inhibitor CCG‐257081 and anti‐PD1 in vivo and to examine its effects on the melanoma immune microenvironment. Because MRTF pathway activation upregulates the expression of immune checkpoint inhibitor genes/proteins, we asked whether CCG‐257081 can improve the response to immune checkpoint blockade. CCG‐257081 reduced the expression of PDL1 in BRAFi‐resistant melanoma cells and decreased surface PDL1 levels on both BRAFi‐sensitive and ‐resistant melanoma cells. Using our recently described murine vemurafenib‐resistant melanoma model, we found that CCG‐257081, in combination with anti‐PD1 immune therapy, reduced tumor growth and increased survival. Moreover, anti‐PD1/CCG‐257081 co‐treatment increased infiltration of CD8+ T cells and B cells into the tumor microenvironment and reduced tumor‐associated macrophages. Here, we propose CCG‐257081 as an anti‐resistance and immune therapy‐enhancing anti‐melanoma agent.

07 Sep 2023·International journal of molecular sciences

Role of Rho/MRTF in Aggressive Vemurafenib-Resistant Murine Melanomas and Immune Checkpoint Upregulation.

Article

Author: Foda, Bardees M ; Neubig, Richard R

Cutaneous melanoma is the deadliest skin cancer. Most have Ras-MAPK pathway (BRAF^V600E or NRAS) mutations and highly effective targeted therapies exist; however, they and immune therapies are limited by resistance, in part driven by small GTPase (Rho and Rac) activation. To facilitate preclinical studies of combination therapies to provide durable responses, we describe the first mouse melanoma lines resistant to BRAF inhibitors. Treatment of mouse lines, YUMM1.7 and YUMMER, with vemurafenib (Vem), the BRAF^V600E-selective inhibitor, resulted in high-level resistance (IC₅₀ shifts 20-30-fold). Resistant cells showed enhanced activation of Rho and the downstream transcriptional coactivator, myocardin-related transcription factor (MRTF). Resistant cells exhibited increased stress fibers, nuclear translocation of MRTF-A, and an increased MRTF-A gene signature. Pharmacological inhibition of the Rho/MRTF pathway using CCG-257081 reduced viability of resistant lines and enhanced sensitivity to Vem. Remarkably, co-treatment of parental lines with Vem and CCG-257081 eliminated resistant colony development. Resistant cells grew more slowly in vitro, but they developed highly aggressive tumors with a shortened survival of tumor-bearing mice. Increased expression of immune checkpoint inhibitor proteins (ICIs) in resistant lines may contribute to aggressive in vivo behavior. Here, we introduce the first drug-resistant mouse melanoma models for assessing combinations of targeted and immune therapies.

01 Dec 2022·Pharmacology Research & Perspectives

Prevention of bleomycin‐induced lung fibrosis via inhibition of the MRTF/SRF transcription pathway

Article

Author: Pawelec, Kendell M. ; Harkema, Jack R. ; Auerbach, Bruce ; Larsen, Scott D. ; Neubig, Richard R. ; Varnum, Megan

AbstractBleomycin‐induced lung fibrosis is a debilitating disease, linked to high morbidity and mortality in chemotherapy patients. The MRTF/SRF transcription pathway has been proposed as a potential therapeutic target, as it is critical for myofibroblast differentiation, a hallmark of fibrosis. In human lung fibroblasts, the MRTF/SRF pathway inhibitor, CCG‐257081, effectively decreased mRNA levels of downstream genes: smooth muscle actin and connective tissue growth factor, with IC50s of 4 and 15 μM, respectively. The ability of CCG‐257081 to prevent inflammation and fibrosis, measured via pulmonary collagen content and histopathology, was tested in a murine model of bleomycin‐induced lung fibrosis. Animals were given intraperitoneal bleomycin for 4 weeks and concurrently dosed with CCG‐257081 (0, 10, 30, and 100 mg/kg PO), a clinical anti‐fibrotic (nintedanib) or the clinical standard of care (prednisolone). Mice treated with 100 mg/kg CCG‐257081 gained weight vs. vehicle‐treated control mice, while those receiving nintedanib and prednisolone lost significant weight. Hydroxyproline content and histological findings in tissue of animals on 100 mg/kg CCG‐257081 were not significantly different from naive tissue, indicating successful prevention. Measures of tissue fibrosis were comparable between CCG‐257081 and nintedanib, but only the MRTF/SRF inhibitor decreased plasminogen activator inhibitor‐1 (PAI‐1), a marker linked to fibrosis, in bronchoalveolar lavage fluid. In contrast, prednisolone led to marked increases in lung fibrosis by all metrics. This study demonstrates the potential use of MRTF/SRF inhibitors to prevent bleomycin‐induced lung fibrosis in a clinically relevant model of the disease.

100 Deals associated with CCG-257081

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Indication	Highest Phase	Country/Location	Organization	Date
Pneumonia	Preclinical	US	Fibrosix, Inc.	-
Pulmonary Fibrosis	Preclinical	US	Fibrosix, Inc.	-

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