The clinically relevant CHK1 inhibitor MK-8776 induces the degradation of the oncogenic protein PML-RARα and overcomes ATRA resistance in acute promyelocytic leukemia cells

Franza, Maria; Albanesi, Jacopo; Mancini, Benedetta; Pennisi, Rosa; Leone, Stefano; Acconcia, Filippo; Bianchi, Fabrizio; di Masi, Alessandra

doi:10.1016/j.bcp.2023.115675

Cited by 1 publication

(1 citation statement)

References 112 publications

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“…The Bradford protein assay kit, anti-mouse, and anti-rabbit secondary antibodies were obtained from Bio-Rad (Hercules, CA). Antibodies against ERα (F-10, mouse) 17 , pS2 (FL-84, rabbit) 17 , cyclin D1 (H-295 rabbit) 13 , ALK (F-12, mouse) (esiRNA validates it in this work), and RARA (C-1, mouse) 44 were obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Additionally, anti-MELK (ab273015, rabbit) (esiRNA validates it in this work) and anti-BDNF (ab108319, rabbit) 45 antibodies were purchased from Abcam (Cambridge, UK).…”

Section: Methodsmentioning

confidence: 79%

Selective impact of ALK and MELK inhibition on ERα stability and cell proliferation in cell lines representing distinct molecular phenotypes of breast cancer

Bartoloni,

Pescatori,

Bianchi

et al. 2024

Sci Rep

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Breast cancer (BC) is a leading cause of global cancer-related mortality in women, necessitating accurate tumor classification for timely intervention. Molecular and histological factors, including PAM50 classification, estrogen receptor α (ERα), breast cancer type 1 susceptibility protein (BRCA1), progesterone receptor (PR), and HER2 expression, contribute to intricate BC subtyping. In this work, through a combination of bioinformatic and wet lab screenings, followed by classical signal transduction and cell proliferation methods, and employing multiple BC cell lines, we identified enhanced sensitivity of ERα-positive BC cell lines to ALK and MELK inhibitors, inducing ERα degradation and diminishing proliferation in specific BC subtypes. MELK inhibition attenuated ERα transcriptional activity, impeding E2-induced gene expression, and hampering proliferation in MCF-7 cells. Synergies between MELK inhibition with 4OH-tamoxifen (Tam) and ALK inhibition with HER2 inhibitors revealed potential therapeutic avenues for ERα-positive/PR-positive/HER2-negative and ERα-positive/PR-negative/HER2-positive tumors, respectively. Our findings propose MELK as a promising target for ERα-positive/PR-positive/HER2-negative BC and highlight ALK as a potential focus for ERα-positive/PR-negative/HER2-positive BC. The synergistic anti-proliferative effects of MELK with Tam and ALK with HER2 inhibitors underscore kinase inhibitors’ potential for selective treatment in diverse BC subtypes, paving the way for personalized and effective therapeutic strategies in BC management.

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Section: Methodsmentioning

confidence: 79%