Mcl-1 inhibition overcomes intrinsic and acquired Regorafenib resistance in Colorectal Cancer

Song, Xiangping; Shen, Lin; Tong, Jingshan; Kuang, Chaoyuan; Zeng, Shan; Schoen, Robert E.; Yu, Jian; Pei, Haiping; Zhang, Lin

doi:10.7150/thno.45363

Cited by 56 publications

(40 citation statements)

References 43 publications

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“…Decreased degradation of MCL-1 is involved in the E3 ubiquitin ligase FBW7 mutation-induced resistance to regorafenib in colorectal cancer patients [ 144 ]. The MCL-1 inhibitor S63845, AZD5991, AMG-176 restore sensitivity to regorafenib in FBW7 mutant colorectal cancer cells by restoring the apoptotic response [ 145 ]. In BRAF V600E -mutant colorectal cancer, mutant BRAF upregulates MCL-1 to confer apoptosis resistance [ 146 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting MCL-1 in cancer: current status and perspectives

et al. 2021

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Myeloid leukemia 1 (MCL-1) is an antiapoptotic protein of the BCL-2 family that prevents apoptosis by binding to the pro-apoptotic BCL-2 proteins. Overexpression of MCL-1 is frequently observed in many tumor types and is closely associated with tumorigenesis, poor prognosis and drug resistance. The central role of MCL-1 in regulating the mitochondrial apoptotic pathway makes it an attractive target for cancer therapy. Significant progress has been made with regard to MCL-1 inhibitors, some of which have entered clinical trials. Here, we discuss the mechanism by which MCL-1 regulates cancer cell apoptosis and review the progress related to MCL-1 small molecule inhibitors and their role in cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Targeting MCL-1 in cancer: current status and perspectives

et al. 2021

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“…Myeloid cell leukemia 1 (MCL-1), an antiapoptotic B-cell lymphoma 2 (Bcl-2) family protein, blocks intrinsic pathway-initiated apoptosis by interfering with BAX–BAK interaction. The increased expression of MCL-1 has been observed in human cancers and has been associated with the induction of resistance to chemo-radiotherapy and targeting therapy [ 32 , 33 , 34 ]. The inhibition of MCL-1 expression has been indicated to reverse regorafenib resistance in CRC cells through the restoration of regorafenib-induced apoptosis [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…The increased expression of MCL-1 has been observed in human cancers and has been associated with the induction of resistance to chemo-radiotherapy and targeting therapy [ 32 , 33 , 34 ]. The inhibition of MCL-1 expression has been indicated to reverse regorafenib resistance in CRC cells through the restoration of regorafenib-induced apoptosis [ 34 ]. Our data showed that siMCL-1 effectively enhanced the regorafenib-mediated inhibition of the growth of HCC cells ( Figure 2 H,I).…”

Section: Discussionmentioning

confidence: 99%

Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma

Chen

Hsu

Chen

et al. 2021

Cancers

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While regorafenib was approved for the treatment of advanced HCC in 2017, with a partial response and survival benefit; other combination agents to facilitate the efficacy of regorafenib still need to be explored. Magnolol is a potential natural anti-tumor compound for many types of cancers. Combination indexes calculated on the basis of both in vitro and in vivo models have indicated a synergistic effect of the combination of regorafenib and magnolol. The overexpression of the VEGF-A protein significantly diminished regorafenib’s inhibition of cell viability, while the transient knockdown of VEGF-A by siRNA effectively sensitized HCC cells to regorafenib. In addition, the inhibition of MCL-1 by siRNA combined with regorafenib allowed for a significantly greater inhibition of cell growth, compared to regorafenib alone. A lower protein expression level for VEGF-A and MCL-1 was found for the combination treatment of HCC in vitro and in vivo. A superior metastasis inhibition was also found in the combination group, as compared to the single-treatment groups, using a transwell assay, wound healing assay, and Western blotting. The caspase-dependent and -independent and DNA damage effects, as determined by flow cytometry and a comet assay, were increased by the combination therapy. Taken together, magnolol sensitized HCC to regorafenib, which was correlated with the reduction of VEGF-A and MCL-1 and the induction of apoptosis.

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“…By interaction with the proapoptotic proteins such as Bak or Bax, Mcl-1 is able to disrupt the mitochondrial membrane and ultimately prevents apoptosis [ 17 ]. Mcl-1 is frequently overexpressed in various cancers including ESCC [ 29 , 30 ], and it protects tumor cells from apoptosis induced by chemotherapeutic agents, such as cytarabine, daunorubicin, and regorafenib [ 31 , 32 ]. Knockdown of Mcl-1 by shRNA or selective inhibitor UMI-77 greatly enhances the sensitivity of ESCC cells to CDDP [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional inhibition by CDK7/9 inhibitor SNS-032 suppresses tumor growth and metastasis in esophageal squamous cell carcinoma

et al. 2021

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Metastasis is one of most lethal causes that confer a poor prognosis of patients with esophageal squamous cell carcinoma (ESCC), whereas there is no available target drug for metastatic ESCC currently. In this study, we aimed to determine whether the transcriptional inhibition by CDK7/9 inhibitor SNS-032 is activity against ESCC. MTT and soft agar assays were performed to examine the influence of SNS-032 on ESCC growth in vitro. Tumor xenograft in nude mice was used to assess the antitumor activity of SNS-032 in vivo. The roles of SNS-032 in ESCC metastasis were conducted by wound healing and transwell assays in vitro, and by a lung and a popliteal lymph node metastasis model in vivo. The results showed that CDK7 and CDK9 were highly expressed in ESCC cells; SNS-032 effectively inhibited cellular viability, abrogated anchorage-independent growth, and potentiated the sensitivity to cisplatin in ESCC cells in vitro and in vivo. In addition, SNS-032 induced a mitochondrial-dependent apoptosis of ESCC cells by reducing Mcl-1 transcription. SNS-032 also potently abrogated the abilities of ESCC cell migration and invasion through transcriptional downregulation of MMP-1. Importantly, SNS-032 remarkably inhibited the growth of ESCC xenograft, increased the overall survival, as well as diminished the lung and lymph node metastasis in nude mice. Taken together, our findings highlight that the CDK7/9 inhibitor SNS-032 is a promising therapeutic agent, and warrants a clinical trial for its efficacy in ESCC patients, even those with metastasis.

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Mcl-1 inhibition overcomes intrinsic and acquired Regorafenib resistance in Colorectal Cancer

Cited by 56 publications

References 43 publications

Targeting MCL-1 in cancer: current status and perspectives

Targeting MCL-1 in cancer: current status and perspectives

Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma

Transcriptional inhibition by CDK7/9 inhibitor SNS-032 suppresses tumor growth and metastasis in esophageal squamous cell carcinoma

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