The mortality rate of ovarian cancer ranks first among gynecological malignancies. Most patients with ovarian cancer are not diagnosed until the advanced stages, and over the past few decades, the standard treatment regimen for patients with advanced ovarian cancer has been to use cytoreductives in combination with chemotherapy drugs such as platinum, with an overall five-year survival rate of between 30% and 50%[1]. Although most patients respond well to first-line chemotherapy, more than 75% develop resistance and relapse within 5 years [2]. Therefore, there is an urgent need to develop new treatment strategies to improve the survival rate of patients with advanced ovarian cancer.
Cancer genome atlas (tcga) data show that about 30% of patients with advanced ovarian cancer have overactivated mapk signaling pathways [3], suggesting that mapk signaling pathways may be potential drug targets for ovarian cancer. Trametinib is a non-competitive second-generation MEK1/2 inhibitor (MEKI) with high specificity that was approved by the FDA in 2013 for the clinical treatment of advanced melanoma, and is expected to be used in the treatment of other tumors with abnormal activation of the mapk signaling pathway, including ovarian cancer, given its significant clinical efficacy. At present, a number of clinical trials and basic studies have shown that meki has a good therapeutic effect on ovarian cancer, such as a number of clinical trial results show that meki can effectively alleviate the condition of patients with low-grade serous ovarian cancer [4]. In addition, it has been suggested that abnormal activation of the mapk signaling pathway can be used as a poor prognostic indicator in patients with high-grade serous ovarian cancer [5]. However, there have been few articles systematically evaluating the efficacy of meki in the treatment of advanced ovarian cancer.
On August 31, 2021, Tan Jing's group from the Center for Cancer Prevention and Control of Sun Yat-sen University and the State Key Laboratory of South China Oncology published a paper entitled "Targeting Enhancer reprogramming to mitigate mek inhibitor resistance in preclinical models" in the journal of clinical investigation online Advanced ovarian cancer research paper, which comprehensively uses advanced ovarian cancer model construction, large-scale sequencing and functional experimental verification, systematically explores the therapeutic potential of MEK inhibitors in ovarian cancer, and elucidates the resistance mechanism of mek inhibitors, that is, enhancer reprogramming mediates the expression downregulation of negatively regulated genes of the mapk signaling pathway, which in turn leads to the reactivation of the mapk signaling pathway. Finally, a therapeutic strategy for combining HDAC inhibitors to effectively overcome MEK inhibitor resistance was proposed.
In order to systematically study the anti-tumor activity and clinical relevance of MEK inhibitors to ovarian cancer, the researchers first constructed 20 patient-derived advanced ovarian cancer primary cells, and detected the sensitivity of these primary cells and commercial cell lines to MEK inhibitors, and the results showed that MEK inhibitors can effectively inhibit ovarian cancer proliferation and induce apoptosis, have good anti-tumor activity, and also have drug resistance. In order to explore the mechanism of drug resistance, the researchers compared the activity changes of the mapk pathway of sensitive and resistant cell lines after trameinib treatment, and found that compared with sensitive cells, the erk activity in drug-resistant cells did not decrease significantly after trametinib treatment, and its activity recovered significantly with the prolongation of treatment time, suggesting that ovarian cancer resistance to mek inhibitors may be related to the reactivation of tumor mapk signaling pathway. The researchers' analysis of the database of cosmic (catalogue of somatic mutations in cancer) and ccle (cancer cell line encyclopedia) found no significant difference in mutations in mapk signaling pathway-related genes in drug-resistant and susceptible ovarian cancer cell lines, indicating that the genetic mutations were not involved in the inherent resistance and acquired resistance of meki. Epigenetic alterations may have mediated the reactivation of the mapk signaling pathway. In addition, the researchers also saw similar phenomena in the two acquired drug-resistant cell lines, that is, there was also a significant reactivation of erk activity in the acquired drug-resistant cell line and mutations in the mapk signaling pathway related genes did not differ significantly in the drug-sensitive and acquired drug-resistant cells, further indicating that epigenetic regulation may mediate the reactivation of mapk signaling in drug-resistant cells.
To this end, the researchers detected the difference between drug-resistant cell lines and sensitive cell lines at the epigenetic level by chip-seq, found that there was significant enhancer remodeling in drug-resistant cells, and found that the changes in enhancers h3k27ac were highly consistent with the multiple changes in transcriptional level expression through integrated analysis with RNA-seq data, and the mapk signaling pathway was significantly enriched. It is worth noting that in drug-resistant cells, the genes of the enhancer h3k27ac signal downregulation are mainly involved in the negative feedback inhibition regulation of the mek/erk signal, suggesting that the downregulation of the negative regulators of the mapk pathway may be involved in the resistance of mek inhibitors. In addition, through epigenetic small molecule drug screening, the researchers further found that most HDAC inhibitors can significantly overcome MEK inhibitor resistance and can reverse the reactivation of ERK in drug-resistant cell lines. Further studies have found that HDAC inhibitors upregulate the expression of mapk negative regulators by changing enhancer reprogramming, thereby inhibiting the recovery of drug-resistant cell lines erk, and ultimately reversing the resistance of MEK inhibitors. In vivo experiments have also further confirmed the synergistic antitumor effect of the combination of HDAC inhibitors and trameinib.
In summary, the researchers systematically investigated the therapeutic efficacy of mek inhibitors in clinical models of advanced ovarian cancer, and also elucidated that drug resistance to mek inhibitors is associated with reactivation of the erk signaling pathway caused by enhancer reprogramming. HDAC inhibitors can overcome resistance to trammetinib by reversing enhancer reprogramming, while targeting epigenetic pathways and mapk signaling pathways may provide an effective therapeutic strategy for advanced ovarian cancer.
Enhancer reprogramming mediates resistance to MEK inhibitors in the treatment of advanced ovarian cancer
Dr. Shi Ni Liu, Technician Zou Qiong, and Postdoctoral Fellow Chen Jieping are the co-first authors of this paper, and dr. Jing Tan of the Center for Cancer Prevention and Control, Sun Yat-sen University, and dr. Jihong Liu, Director of the Department of Gynecology, Director Xiong Ying, and Professor Yu Qiang from the Singapore Genomics Institute and Professor Bin-Teanteh of the National Cancer Centre of Singapore.
Researcher Tan Jing has long been committed to the study of the molecular mechanism of tumor treatment resistance and the identification of novel molecular markers, and the construction and screening of new anti-cancer drug platforms in combination with tumor genetics and epigenetics. In recent years, his research results have been published in a series of high-level international journals such as cancer discovery, cancer cell, nature genetics, the journal of clinical investigation, leukemia, advanced science, genes & development, cancer research, etc. Tan Jing's team has been recruiting postdoctoral fellows for many years.