Platinum-resistant ovarian cancer: From drug resistance mechanisms to liquid biopsy-based biomarkers for disease management

Khan, Mohammad Aslam; Vikramdeo, Kunwar Somesh; Sudan, Sarabjeet Kour; Singh, Seema; Wilhite, Annelise; Dasgupta, Santanu; Rocconi, Rodney P.; Singh, Ajay P.

doi:10.1016/j.semcancer.2021.08.005

Cited by 28 publications

(14 citation statements)

References 174 publications

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“…The acquisition of drug resistance is a very complex process mediated by gene mutations, changes in gene expression, selective splicing, post-translational protein modification, etc (Aleksakhina et al, 2019;Khan et al, 2021;Patra et al, 2021;Peixoto da Silva et al, 2021). Sestrins (SESNs) are highly conserved chaperones that play an important role in cell survival (Crisol et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma

Tang

Wei

Tian

et al. 2021

Front. Cell Dev. Biol.

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One contributor to the high mortality of osteosarcoma is its reduced sensitivity to chemotherapy, but the mechanism involved is unclear. Improving the sensitivity of osteosarcoma to chemotherapy is urgently needed to improve patient survival. We found that chemotherapy triggered apoptosis of human osteosarcoma cells in vitro and in vivo; this was accompanied by increased Sestrin2 expression. Importantly, autophagy was also enhanced with increased Sestrin2 expression. Based on this observation, we explored the potential role of Sestrin2 in autophagy of osteosarcoma. We found that Sestrin2 inhibited osteosarcoma cell apoptosis by promoting autophagy via inhibition of endoplasmic reticulum stress, and this process is closely related to the PERK-eIF2α-CHOP pathway. In addition, our study showed that low Sestrin2 expression can effectively reduce autophagy of human osteosarcoma cells after chemotherapy, increase p-mTOR expression, decrease Bcl-2 expression, promote osteosarcoma cell apoptosis, and slow down tumour progression in NU/NU mice. Sestrin2 activates autophagy by inhibiting mTOR via the PERK-eIF2α-CHOP pathway and inhibits apoptosis via Bcl-2. Therefore, our results explain one underlying mechanism of increasing the sensitivity of osteosarcoma to chemotherapy and suggest that Sestrin2 is a promising gene target.

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Section: Introductionmentioning

confidence: 99%

Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma

Tang

Wei

Tian

et al. 2021

Front. Cell Dev. Biol.

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“…The genes encoding HDAC1 (histone deacetylase 1) and DNA demethylase TET1 (tet methylcytosine dioxygenase 1) were DEGs, and the EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) gene associated with DMPs was also DEG in carboplatin-resistant cell lines. Previous studies reported that EZH2 was generally overexpressed and implicated in the advanced stage, platinum resistance, and poor patient survival in OC [ 88 ]. Taken together, these data demonstrate an intrinsic connection between lncRNAs and disrupted epigenetic regulation of gene expression associated with carboplatin-resistance.…”

Section: Discussionmentioning

confidence: 99%

The Long Non-Coding RNA SNHG12 as a Mediator of Carboplatin Resistance in Ovarian Cancer via Epigenetic Mechanisms

Abildgaard

Canto

Rainho

et al. 2022

Cancers

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Genetic and epigenetic changes contribute to intratumor heterogeneity and chemotherapy resistance in several tumor types. LncRNAs have been implicated, directly or indirectly, in the epigenetic regulation of gene expression. We investigated lncRNAs that potentially mediate carboplatin-resistance of cell subpopulations, influencing the progression of ovarian cancer (OC). Four carboplatin-sensitive OC cell lines (IGROV1, OVCAR3, OVCAR4, and OVCAR5), their derivative resistant cells, and two inherently carboplatin-resistant cell lines (OVCAR8 and Ovc316) were subjected to RNA sequencing and global DNA methylation analysis. Integrative and cross-validation analyses were performed using external (The Cancer Genome Atlas, TCGA dataset, n = 111 OC samples) and internal datasets (n = 39 OC samples) to identify lncRNA candidates. A total of 4255 differentially expressed genes (DEGs) and 14529 differentially methylated CpG positions (DMPs) were identified comparing sensitive and resistant OC cell lines. The comparison of DEGs between OC cell lines and TCGA-OC dataset revealed 570 genes, including 50 lncRNAs, associated with carboplatin resistance. Eleven lncRNAs showed DMPs, including the SNHG12. Knockdown of SNHG12 in Ovc316 and OVCAR8 cells increased their sensitivity to carboplatin. The results suggest that the lncRNA SNHG12 contributes to carboplatin resistance in OC and is a potential therapeutic target. We demonstrated that SNHG12 is functionally related to epigenetic mechanisms.

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“…Patients with PARPi resistance have been found to have reversions in RAD51C and RAD51D, and in vitro studies have demonstrated loss of TP53 binding protein 1 [3,46] . Studies of TP53 vary regarding its utility as a marker in platinum resistance, but it may be helpful in treatment planning [47] . Pump P-glycoprotein (P-gp) expression, which is related to drug efflux and multidrug resistance, has also been implicated in PARPi resistance [3,48] .…”

Section: Biomarkersmentioning

confidence: 99%

Ovarian cancer resistance to PARPi and platinum-containing chemotherapy

Summey¹,

Uyar²

2022

Cancer Drug Resist

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Epithelial ovarian cancer remains the most lethal female malignancy despite options for systemic therapy and the emergence of targeted therapies. Although initial response to therapy is observed, recurrence and ultimately chemoresistance result in overall therapeutic failure. This pattern has been evident with platinum therapy since the 1980s. Significant excitement surrounded the approval of poly (ADP-ribose) polymerase inhibition (PARPi) as a novel therapeutic option, especially with the advent of personalized medicine, but resistance has similarly developed to these treatments. Novel agents are constantly being sought, but if the obstacle of chemoresistance remains, the durability of responses will remain tenuous. Unraveling the multifactorial mechanisms of platinum and PARPi resistance is increasingly important as a therapeutic failure with current strategies is almost assured. Focusing greater efforts on expanding the current understanding of the complex nature of platinum and PARPi chemoresistance has tremendous potential to improve clinical outcomes.

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Platinum-resistant ovarian cancer: From drug resistance mechanisms to liquid biopsy-based biomarkers for disease management

Cited by 28 publications

References 174 publications

Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma

Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma

The Long Non-Coding RNA SNHG12 as a Mediator of Carboplatin Resistance in Ovarian Cancer via Epigenetic Mechanisms

Ovarian cancer resistance to PARPi and platinum-containing chemotherapy

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