Molecular Resistance Fingerprint of Pemetrexed and Platinum in a Long-Term Survivor of Mesothelioma
نویسندگان
چکیده
BACKGROUND Pemetrexed, a multi-folate inhibitor combined with a platinum compound is the first-line treatment of malignant mesothelioma, but median survival is still one year. Intrinsic and acquired resistance to pemetrexed is common, but its biological basis is obscure. Here we report for the first time a genome-wide profile of acquired resistance in the tumour from an exceptional case with advanced pleural mesothelioma and almost six years survival after 39 cycles of second-line pemetrexed/carboplatin treatment. METHODOLOGY AND PRINCIPAL FINDINGS Genome-wide analysis with Illumina BeadChip Kit of 25,000 genes was performed on mRNA from pre-treatment and post-resistance biopsies from this individual as well on case and control samples from our previously published study (in total 17 samples). Cell specific expression of proteins encoded by selected genes were analysed by immunohistochemistry. Serial serum levels of CA125, CYFRA21-1 and SMRP levels were examined. TS protein, the main target of pemetrexed was overexpressed. Proteins and genes related to DNA damage response, elongation and telomere extension and repair related directly and indirectly to platinum resistance were overexpressed, as the CHK1 protein and the genes CHEK2, LIG3, POLD1, POLA2, FANCD2, PRPF19, RECQ5 respectively, the last two not previously described in mesothelioma. We observed a down-regulation of leukocyte transendothelial migration and cell adhesion molecules pathways. Silencing of NT5C in two mesothelioma cell lines did not sensitize the cells to Pemetrexed. Proposed resistance markers are TS, KRT7/ CK7, TYMP/ thymidine phosphorylase and down-regulated SPARCL1 and CDKN1B. Moreover, comparison of the primary expression of the sensitive versus a primary resistant case showed multi-fold overexpressed DNA repair, cell cycle, cytokinesis, and spindle formation in the latter. Serum CA125 and SMRP reflected the clinical and radiological course and tumour burden. CONCLUSIONS Genome-wide microarray of mesothelioma pre- and post-resistance biopsies indicated a novel resistance signature to pemetrexed/carboplatin that deserve validation in a larger cohort.
منابع مشابه
Indolent peritoneal mesothelioma: PI3K-mTOR inhibitors as a novel therapeutic strategy
Peritoneal mesothelioma (MPeM) is a scarce abdominal-pelvic malignancy that presents with non-specific features and exhibits a wide clinical spectrum from indolent to aggressive disease. Due to it being a rare entity, there is a lack of understanding of its molecular drivers. Most treatment data are from limited small studies or extrapolated from pleural mesothelioma. Standard treatment include...
متن کاملLong term survival after trimodal therapy in malignant pleural mesothelioma.
PRINCIPLES Trimodal therapy results in long term survival in a small fraction of patients with malignant pleural mesothelioma, particularly in patients having epithelial histology, R0-resection and no nodal involvement. This study analyses the outcome after trimodal therapy including extrapleural pneumonectomy. METHODS From 2000 to 2005 41 patients with histologically verified malignant pleur...
متن کاملSystemic chemotherapy with pemetrexed and cisplatin for malignant peritoneal mesothelioma: a single institution experience.
BACKGROUND AND AIMS Primary malignant peritoneal mesothelioma is a rare malignancy with an unfavorable prognosis. Pemetrexed has proven effective in the treatment of malignant mesothelioma, alone or in combination with platinum agents. In the present study, chemo-naïve patients were evaluated for the efficacy and safety of the pemetrexed-cisplatin combination. METHODS Six patients with diffus...
متن کاملCisplatin and Pemetrexed Activate AXL and AXL Inhibitor BGB324 Enhances Mesothelioma Cell Death from Chemotherapy
Reactive oxygen species (ROS) can promote or inhibit tumorigenesis. In mesothelioma, asbestos exposure to serous membranes induces ROS through iron content and chronic inflammation, and ROS promote cell survival signaling in mesothelioma. Moreover, a current chemotherapy regimen for mesothelioma consisting of a platinum and antifolate agent combination also induce ROS. Mesothelioma is notorious...
متن کاملThe Role of Thymidylate Synthase in Pemetrexed-Resistant Malignant Pleural Mesothelioma Cells
We established new pemetrexed-resistant cells originating from malignant pleural mesothelioma MSTO-211H cells to clarify the mechanism involved in pemetrexed resistance in malignant pleural mesothelioma. In the pemetrexed-resistant cells, only thymidylate synthase (TYMS) mRNA was overexpressed among other well-known molecular targets and chemosensitivity determinants of pemetrexed, and the role...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 7 شماره
صفحات -
تاریخ انتشار 2012