RNA Sequencing of Carboplatin- and Paclitaxel-Resistant Endometrial Cancer Cells Reveals New Stratification Markers and Molecular Targets for Cancer Treatment

Abstract

Despite advances in surgical technique and adjuvant treatment, endometrial cancer has recently seen an increase in incidence and mortality in the USA. The majority of endometrial cancers can be cured by surgery alone or in combination with adjuvant chemo- or radiotherapy; however, a subset of patients experience recurrence for reasons that remain unclear. Recurrence is associated with chemoresistance to carboplatin and paclitaxel and consequentially, high mortality. Understanding the pathways involved in endometrial cancer chemoresistance is paramount for the identification of biomarkers and novel molecular targets for this disease. Here, we generated the first matched pairs of carboplatin-sensitive/carboplatin-resistant and paclitaxel-sensitive/paclitaxel-resistant endometrial cancer cells and subjected them to bulk RNA sequencing analysis. We found that 45 genes are commonly upregulated in carboplatin- and paclitaxel-resistant cells as compared to controls. Of these, the leukemia inhibitory factor, (LIF), the protein tyrosine phosphatase type IVA, member 3 (PTP4A3), and the transforming growth factor beta 1 (TGFB1) showed a highly significant correlation between expression level and endometrial cancer overall survival (OS) and can stratify the 545 endometrial cancer patients in the TCGA cohort into a high-risk and low-risk-cohorts. Additionally, four genes within the 45 upregulated chemoresistance-associated genes are ADAMTS5, MICAL2, STAT5A, and PTP4A3 codes for proteins for which small-molecule inhibitors already exist. We identified these proteins as molecular targets for chemoresistant endometrial cancer and showed that treatment with their correspondent inhibitors effectively killed otherwise chemoresistant cells. Collectively, these findings underline the utility of matched pair of chemosensitive and chemoresistant cancer cells to identify markers for endometrial cancer risk stratification and to serve as a pharmacogenomics model for identification of alternative chemotherapy approaches for treatment of patients with recurrent disease.

Therapeutic Implications of TGFβ in Cancer Treatment: A Systematic Review

“…The PTP4A3 inhibitor here employed was pentamidine, an FDA-approved antifungal, and antiprotozoal agent. In the reviewed article, the treatment of carboplatin-and paclitaxel-resistant endometrial cells with pentamidine repressed cell viability in a dose-dependent manner [93]. This is consistent with the anticancer activity of pentamidine previously shown in human cancer lines and preclinical models of human cancers [97].…”

“…A direct target of TGFβ signaling that has been inhibited in cancer treatment is PTP4A3 [93]. The loss of signaling by TGFβ during cancer progression causes the activation of the cell survival pathway PI3K/AKT mediated by PTP4A3, which can selectively promote metastasis.…”

Targeting LIF/LIFR signaling in cancer

“… 11 LIF is a commonly upregulated gene in carboplatin- and paclitaxel-resistant cells and its expression correlates with poor outcome in ECa patients. 50 Additionally, LIF/LIFR signaling contributes to drug-resistant OCa. 51 Autocrine and paracrine LIF signaling is shown to promote chemoresistance in cholangiocarcinoma by up-regulating Mcl-1 via a novel STAT3-PI3K/AKT-dependent pathway.…”

LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer

“…Obese people have unusually high levels of leptin; and leptin increases p-STAT3, LIF, LIFR, levels in cultured human endometrial cells [ 21 ]. LIF is a commonly upregulated gene in carboplatin- and paclitaxel-resistant cells and its expression correlates with poor outcome in EC patients [ 23 ]. Collectively, these findings suggest that LIF/LIFR may function as a novel therapeutic target for EC, however, its role and mechanisms in the progression of EC remain elusive.…”