YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells

Abstract

Cancer stem cell survival is the leading factor for tumor recurrence after tumor-suppressive treatments. Therefore, specific and efficient inhibitors of cancer stemness must be discovered for reducing tumor recurrence. YM155 has been indicated to significantly reduce stemness-derived tumorsphere formation. However, the pharmaceutical mechanism of YM155 against cancer stemness is unclear. This study investigated the potential mechanism of YM155 against cancer stemness in lung cancer. Tumorspheres derived from epidermal growth factor receptor (EGFR)-mutant HCC827 and EGFR wild-type A549 cells expressing higher cancer stemness markers (CD133, Oct4, and Nanog) were used as cancer stemness models. We observed that EGFR autophosphorylation (Y1068) was higher in HCC827- and A549-derived tumorspheres than in parental cells; this autophosphorylation induced tumorsphere formation by activating G9a-mediated stemness. Notably, YM155 inhibited tumorsphere formation by blocking the autophosphorylation of EGFR and the EGFR-G9a-mediated stemness pathway. The chemical and genetic inhibition of EGFR and G9a revealed the significant role of the EGFR-G9a pathway in maintaining the cancer stemness property. In conclusion, this study not only revealed that EGFR could trigger tumorsphere formation by elevating G9a-mediated stemness but also demonstrated that YM155 could inhibit this formation by simultaneously blocking EGFR autophosphorylation and G9a activity, thus acting as a potent agent against lung cancer stemness.

Integrative analysis of gene expression and DNA methylation through one‐class logistic regression machine learning identifies stemness features in medulloblastoma

“…We interrogated CMap utilizing the gene expression signatures from SHH MB samples with high and low mRNAsi levels. The CMap analysis precisely identified some compounds that have been shown to specifically impact CSCs in other tumor types (Angeletti et al ., ; Batsaikhan et al ., ; Battula et al ., ; Bonuccelli et al ., ; Bozok Cetintas et al ., ; Chen et al ., , ; Cheng et al ., ; Dominguez‐Gomez et al ., ; Garulli et al ., ; Hong et al ., ; Hou et al ., ; Malkomes et al ., ; Xiang et al ., ; Xu et al ., ; Yeh et al ., ; Yin et al ., ; You et al ., ; Zhang et al ., ; Zheng et al ., ,b). These compounds include the CDK inhibitors palbociclib and alvocidib, the AMPK inhibitor dorsomorphin, the IKK inhibitor BMS‐345541, the smoothened receptor antagonist cyclopamine, the topoisomerase inhibitors topotecan and doxorubicin, the GABA receptor agonist ivermectin, the NF‐κB pathway inhibitor auranofin, the MTOR inhibitor dactolisib, the AKT inhibitors MK‐2206 and pyrvinium‐pamoate, the HMGCR inhibitor simvastatin, the HDAC inhibitors apicidin, vorinostat, and givinostat, and the DNA synthesis inhibitor anisomycin.…”

“…The survival rate of patients with MB largely depends on the molecular and clinical features of the cancer, varying from > 90% 5-year overall survival (OS) for WNT MB patients to < 50% 5-year OS for patients with metastatic group 3 or SHH MB with a TP53 mutation (Ramaswamy et al, 2016a,b). Aggressive yet nonspecific multimodal therapies (surgery, radiation therapy, and chemotherapy) have significantly improved the survival of MB patients, but survivors experience severe late-onset cognitive and neurological side effects, including secondary malignancies (Crawford et al, 2007;Diller et al, 2009;Packer and Vezina, 2008;Packer et al, 2013). The cause of most MB-related deaths is leptomeningeal metastases (Ramaswamy and Taylor, 2017).…”

Identification of synergistic drug combinations using breast cancer patient-derived xenografts

“…Based on our collective findings, we propose that YM155 and afatinib could potentially enhance each other's efficacy in TNBC. Interestingly, YM155 has been shown to reduce EGFR expression and tumor cell proliferation and survival in pancreatic cancer 81 as well as EGFR-positive non-small cell lung cancer, in which YM155 was found to be synergistic with afatinib 82 and other EGFR inhibitors 83 , to reverse resistance to the EGFR inhibitor erlotinib in EGFR-mutant lung cancer 84 , and to inhibit EGFR autophosphorylation which promotes lung cancer stemness 85 . The EGFR inhibitor lapatinib was also found to enhance the efficacy of YM155 in neuroblastoma by inhibiting drug efflux through the ABCB1 transporter 86 .…”

Epidermal growth factor induces STAT1 expression to exacerbate the IFNr‐mediated PD‐L1 axis in epidermal growth factor receptor‐positive cancers

“…Cancer is the leading cause of death worldwide. Cancer cells grow uncontrollably because of gene mutations and the amplification of oncogenes, such as the epidermal growth factor (EGF) receptor (EGFR) in lung cancers, that contribute to cell survival, proliferation, and cancer stemness . Because EGFR is demonstrated as a tumor therapeutic target in clinical practice, the EGFR‐mediated signaling cascade has merited thorough investigation.…”