UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

Abstract

Purpose: c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases.Experimental Design: We have analyzed the anti-triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts. Results:We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity.Conclusions: In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC.

c‐Src inhibitor selectively inhibits triple‐negative breast cancer overexpressed Vimentin in vitro and in vivo

“…Expression of high levels of ER and HER2 has been shown to be 2 indicators for resistance to c‐Src inhibitor treatment in breast cancer cell lines . In agreement with this observation, compelling evidence indicates that TNBC cell lines show a high sensitivity to the c‐Src inhibitor . However, clinical trials indicate a controversial result in TNBC patients treated with the c‐Src inhibitor with a lower rate of benefit .…”

“…16 In agreement with this observation, compelling evidence indicates that TNBC cell lines show a high sensitivity to the c-Src inhibitor. [16][17][18][19] However, clinical trials indicate a controversial result in TNBC patients treated with the c-Src inhibitor with a lower rate of benefit. [20][21][22] This implies that more factors are involved in TNBC to affect the function of c-Src, in addition to the traditional biomarkers: This suggests that vimentin is an important biomarker to predict the therapeutic effects of the c-Src inhibitor in TNBC patients.…”

“…c‐Src inhibitors can actively suppress tumor cell growth in the breast, colon, ovaries, and liver . A large number of studies have indicated that TNBC shows higher sensitivity to the c‐Src inhibitor than do other cancer subgroups . It has been proven that ER and HER2 expression levels affect the therapeutic effects of the c‐Src inhibitor in breast cancer cell lines .…”

“…[13][14][15] A large number of studies have indicated that TNBC shows higher sensitivity to the c-Src inhibitor than do other cancer subgroups. [16][17][18][19] It has been proven that ER and HER2 expression levels affect the therapeutic effects of the c-Src inhibitor in breast cancer cell lines. 16 Unfortunately, patients with TNBC receive limited benefit from c-Src inhibitor treatment.…”

Integration of high-content fluorescence imaging into the metabolic flux assay reveals insights into mitochondrial properties and functions

“…8A ). First, we examined basal OCR values in the breast cancer patient-derived cell model VARI068 54 and followed with Mitotracker staining directly into the XF assay. Our data revealed elevated basal OCR levels in the RhoA KO cell line and lower OCR levels in the RhoC KO cell model ( Fig.…”