scholarly journals Corrigendum to ‘Targeting P4HA1 with a Small Molecule Inhibitor in a Colorectal Cancer PDX Model’ [Translational Oncology 13 (2020) 100754]

2021 ◽  
Vol 14 (11) ◽  
pp. 101142
Author(s):  
Sumit Agarwal ◽  
Michael Behring ◽  
Hyung-Gyoon Kim ◽  
Prachi Bajpai ◽  
Balabhadrapatruni V.S.K. Chakravarthi ◽  
...  
2020 ◽  
Vol 13 (4) ◽  
pp. 100754 ◽  
Author(s):  
Sumit Agarwal ◽  
Michael Behring ◽  
Hyung-Gyoon Kim ◽  
Prachi Bajpai ◽  
Balabhadrapatruni V.S.K. Chakravarthi ◽  
...  

EBioMedicine ◽  
2017 ◽  
Vol 25 ◽  
pp. 22-31 ◽  
Author(s):  
Seung Ho Shin ◽  
Do Young Lim ◽  
Kanamata Reddy ◽  
Margarita Malakhova ◽  
Fangfang Liu ◽  
...  

2019 ◽  
Vol 5 (9) ◽  
pp. eaax2277 ◽  
Author(s):  
Lei Wang ◽  
Lixiao Zhang ◽  
Li Li ◽  
Jingsheng Jiang ◽  
Zhen Zheng ◽  
...  

Disrupting the interactions between Hsp90 and Cdc37 is emerging as an alternative and specific way to regulate the Hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. Here, we identified DDO-5936 as a small-molecule inhibitor of the Hsp90-Cdc37 protein-protein interaction (PPI) in colorectal cancer. DDO-5936 disrupted the Hsp90-Cdc37 PPI both in vitro and in vivo via binding to a previously unknown site on Hsp90 involving Glu47, one of the binding determinants for the Hsp90-Cdc37 PPI, leading to selective down-regulation of Hsp90 kinase clients in HCT116 cells. In addition, inhibition of Hsp90-Cdc37 complex formation by DDO-5936 resulted in a remarkable cyclin-dependent kinase 4 decrease and consequent inhibition of cell proliferation through Cdc37-dependent cell cycle arrest. Together, our results demonstrated DDO-5936 as an identified specific small-molecule inhibitor of the Hsp90-Cdc37 PPI that could be used to comprehensively investigate alternative approaches targeting Hsp90 chaperone cycles for cancer therapy.


2021 ◽  
Vol 12 ◽  
Author(s):  
Andrey Poloznikov ◽  
Sergey Nikulin ◽  
Larisa Bolotina ◽  
Andrei Kachmazov ◽  
Maria Raigorodskaya ◽  
...  

Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new targeted therapy considering limited chemotherapy options. KRAS mutations are the most frequent molecular alterations in CRC. However, there are no approved K-Ras targeted therapies for these tumors yet. GSK-3β is demonstrated to be a critically important kinase for the survival and proliferation of K-Ras–dependent pancreatic cancer cells. In this study, we tested combinations of standard-of-care therapy and 9-ING-41, a small molecule inhibitor of GSK-3β, in CRC cell lines and patient-derived tumor organoid models of CRC. We demonstrate that 9-ING-41 inhibits the growth of CRC cells via a distinct from chemotherapy mechanism of action. Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41–treated CRC cells. Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras–dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC.


2021 ◽  
Vol 10 (6) ◽  
pp. 245-250
Author(s):  
Maricruz Anaya-Ruiz ◽  
Martin Perez-Santos

Inhibition of the PD-1/PD-L1 pathway is a target for the development of new therapies. US10710986 patent describes a small molecule that targets PDL-1/PD-1 interactions and triggers antitumor activity against colorectal cancer. However, it does not describe biological assays that allow us to suppose that this small molecule may be active in other types of cancer. So far, there are no reports of clinical trials to evaluate the safety, toxicity and efficacy, but it will be of great interest to analyze in the future if this compound surpasses the action of therapy in cancer.


Author(s):  
Chaoqun Liu ◽  
Zhihua Pan ◽  
Qian Chen ◽  
Zetao Chen ◽  
Weiwei Liu ◽  
...  

Abstract Background Chemoresistance is the major cause of chemotherapy failure in patients with colorectal cancer (CRC). Protein tyrosine kinase 6 (PTK6) is aberrantly overexpressed in clinical CRC tissues undergoing chemotherapy. We studied if PTK6 contributed to the chemoresistance of CRC in human and mice. Methods We obtained tissue samples from patients with CRC and measured the expression of PTK6 by immunohistochemistry. Gain- and loss-of-function assays were performed to study the biological functions of PTK6. We constructed the FLAG-tagged wild type (WT), kinase-dead, and inhibition-defective recombinant mutants of PTK6 to study the effect phosphorylated activation of PTK6 played on CRC cell stemness and chemoresistance. We used small molecule inhibitor XMU-MP-2 to test the influence of PTK6 on sensitivity of CRC cells to 5-FU/L-OHP in both nude mouse and patient-derived xenograft (PDX) animal models. Results PTK6 is overexpressed in CRC tissues and plays a stimulatory role in the proliferation and chemoresistance of CRC cells both in vitro and in vivo. PTK6, especially the phosphorylated PTK6, can promote the stemness of CRC cells through interacting with JAK2 and phosphorylating it to activate the JAK2/STAT3 signaling. Pharmacological inhibition of PTK6 using XMU-MP-2 effectively reduces the stemness property of CRC cells and improves its chemosensitivity to 5-FU/L-OHP in both nude mice subcutaneously implanted tumor model and PDX model constructed with NOD-SCID mice. Conclusions PTK6 interacts with JAK2 and phosphorylates it to activate JAK2/STAT3 signaling to promote the stemness and chemoresistance of CRC cells. Pharmacological inhibition of PTK6 by small molecule inhibitor dramatically enhances the sensitivity to chemotherapy in nude mice and PDX models.


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