Targeting CDK9 for treatment of colorectal cancer

Abstract

Colorectal cancer (CRC) remains one of the most lethal human malignancies, and pursuit of new therapeutic targets for treatment has been a major research focus. Cyclin‐dependent kinase 9 (CDK9), which plays a crucial role in transcription, has emerged as a target for cancer treatment. CDKI‐73, one of the most potent and pharmacologically superior CDK9 inhibitors, has demonstrated excellent anti‐tumour efficacy against several types of cancers. In this study, we evaluated its therapeutic potential against CRC. CDKI‐73 elicited high cytotoxicity against all colon cancer cell lines tested. Cell cycle and apoptosis analysis in HCT 116 and HT29 cells revealed that CDKI‐73 induced cell death without accumulation of DNA at any phase of the cell cycle. Moreover, it caused depolarisation of mitochondrial membrane, leading to caspase‐independent apoptosis. Knockdown by shRNA demonstrated the CDK9‐targeted mechanism of CDKI‐73, which also affected the Mnk/eIF4E signalling axis. In addition, RT‐qPCR analysis showed that CDKI‐73 down‐regulated multiple pro‐survival factors at the mRNA level. Its in vivo anti‐tumour efficacy was further evaluated in Balb/c nude mice bearing HCT 116 xenograft tumours. CDKI‐73 significantly inhibited tumour growth (***P < 0.001) without overt toxicity. Analysis of the tumour tissues collected from the xenografted animals confirmed that the in vivo anti‐tumour efficacy was associated with CDK9 targeting of CDKI‐73. Overall, this study provides compelling evidence that CDKI‐73 is a promising drug candidate for treating colorectal cancer.

Cyclin‑dependent kinase 9 expression and its association with CD8+ T cell infiltration in microsatellite‑stable colorectal cancer

“…To the best of our knowledge, the present study was the first to evaluate the association of CDK9 and tumor-infiltrating CD8 + T cells in MSS CRC. A number of studies have demonstrated that CDK9/P-TEFb is involved in the cell growth and survival of several types of cancer, including CRC (15,49,50). However, these studies have focused on the cancer cells themselves, ignoring the effect of CDK9 on the TME.…”

“…Cyclin-dependent kinase 9 (CDK9) is a key regulator of transcriptional elongation, which is a promising therapeutic target in cancer, particularly for types of cancer driven by transcriptional dysregulation (13,14). However, the mechanism and clinical transformation of CDK9 in CRC have been rarely reported (15). In addition, it has been demonstrated that APC/BRAF/SMAD4 gene mutations lead to upregulation of transcription, which leads to the occurrence and development of CRC (16–18).…”

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

“…There are some MNK1/2 inhibitors tested in CRC, such as cercosporamide, which suppresses eIF4E phosphorylation in colon cancer cell lines blocking the growth of HCT116 colon carcinoma xenograft tumors [77]; 6-hydroxy-4-methoxy-3-methylbenzofuran-7-carboxamide derivatives compounds 5o and 8k, that also exhibit anti-proliferative activity and block eIF4E phosphorylation in the CRC HCT-116 cell line [82]; 42i, a pyridine-aminal derivative synthesized as MNK1/2 inhibitor that significantly blocks eIF4E phosphorylation in colon cancer CT-26 cell line and inhibits tumor growth in CT-26 allograft model [83] and 4t, a pyridine derivative with anti-proliferative activity against CRC cell lines among others [98]. Targeting different proteins than MNKs, two compounds are found to downregulate MNK1 in CRC, CDKI-73 [142] and metformin [143]. Regarding MNK inhibitors in clinical trials, the MNK1/2 inhibitor eFT508 is being evaluated in phase II in colorectal cancer patients alone or in combination with Avelumab.…”

Expression of cyclin-dependent kinases and their clinical significance with immune infiltrates could predict prognosis in colorectal cancer

“…Cyclin-dependent kinases (CDKs) are such potential biomarkers for the diagnosis of CRC due to their crucial role in the elongation step of the global transcription process [ 2 ]. CDKs and their specific functions in cancer have been comprehensively investigated; they are involved in regulation of the cell cycle by interacting with specific cell-cycle–regulatory cyclins [ 3 ].…”