Molecular resistance fingerprint of pemetrexed and platinum in a long-term survivor of mesothelioma

Our plain-English summary of Molecular resistance fingerprint of pemetrexed and platinum in a long-term survivor of mesothelioma, by O.D. Røe, A. Szulkin, E. Anderssen, et al (PloS One, 2012).

The study

• Authors: O.D. Røe, A. Szulkin, E. Anderssen, A. Flatberg, H. Sandeck, T. Amundsen, S.E. Erlandsen, K. Dobra, S.H. Sundstrøm
• Journal: PloS One
• Published: 2012;7(8):e40521
• Type of article: Case report
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This was a case report of one woman in Norway with advanced pleural mesothelioma of the epithelial type, diagnosed at age 42 in 2003, who survived almost six years. The patient had been a hairdresser for nine years. The hair-dryer used daily was found to contain asbestos coils, which the authors called low-grade asbestos exposure. After earlier chemotherapy, the patient received 39 cycles of pemetrexed and carboplatin until the tumour became resistant. The authors compared tumour gene activity before treatment and after resistance, using 17 samples in total. After resistance, 241 genes were more active and 289 less active. Staining for thymidylate synthase, the main target of pemetrexed, rose from below 1% to 25% of tumour cells. Silencing the gene NT5C in two mesothelioma cell lines did not make the cells more sensitive to pemetrexed. Blood levels of SMRP and CA125 followed the disease course. The authors proposed possible resistance markers, noted that the study involved only one case, and concluded the findings should be confirmed in a larger patient group.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Case report of a single patient, with genome-wide gene expression (microarray) analysis of tumour biopsies taken before treatment and after treatment resistance, immunohistochemistry, serial serum biomarkers, and a gene-silencing experiment in two mesothelioma cell lines
• Who was studied: One 42-year-old woman referred to a Norwegian clinic in May 2003 with malignant mesothelioma of the epithelial type, stage T4N3M0. Her biopsies were analysed alongside mesothelioma and parietal pleura samples from the authors' earlier study, 17 samples in total.
• Exposure: The patient worked nine years as a hairdresser. The department of occupational medicine found that the hair-dryer she used daily contained asbestos coils, and the authors described this as low-grade asbestos exposure. No fiber type is given. The treatment studied was 39 cycles of second-line pemetrexed (500 mg/m2) plus carboplatin.
• Main results:
  • In the tumour samples taken after resistance, 241 genes were overexpressed and 289 were down-regulated compared with before treatment.
  • In the patient's tumour, thymidylate synthase (TYMS) protein staining increased from below 1% to 25% of tumour cells after resistance.
  • In the patient's tumour, staining for the DNA damage response protein CHK1 went from almost undetectable in the first biopsy to 50% after resistance.
  • In the patient's tumour, cytokeratin 7 (CK7) staining showed a 75% increase in the number of stained cells after resistance.
  • Compared with a primary resistant patient from the earlier study who survived only six months, 188 genes (22.7%) were more than 2-fold overexpressed in that resistant case, versus only 22 (2.6%) in this sensitive case.
  • In the two mesothelioma cell lines, silencing NT5C did not produce significant differences in the cells treated with pemetrexed.
  • In the patient's blood, SMRP was 31.33 nM at first (12-fold the normal value of 2.5 nM). It fell to 16.7 nM and rose again after resistance. CA125 was 108 kIE/L at first (3-fold the normal value of 35 kIE/L) and followed a similar course.
• The authors' conclusion: The authors proposed KRT7/CK7, TYMP/thymidine phosphorylase, and down-regulated SPARCL1 and CDKN1B as possible resistance markers. They concluded that the findings should be confirmed in a larger patient cohort with biopsies taken before treatment and after treatment failure.
• Limitations the authors state:
  • The study involved only one case.
  • Microarray analysis of mixed tumour samples reflects tumour plus surrounding tissue, not tumour cells only.
  • Biopsy material was scarce, so only selected immunohistochemistry could be used to confirm the gene findings.
  • In the cell line experiment, the half-life and activity of NT5C and the actual amount of protein left in the silenced cells were unknown, which might affect the outcome.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Mesothelioma, Malignant Mesothelioma, Median Survival, Pleural Mesothelioma, Carboplatin, Immunohistochemistry, Soluble Mesothelin-Related Peptides (SMRP).

Related studies

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• Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines — M. Kitazono-Saitoh, Y. Takiguchi, et al. (2012)
• Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed — L. Cortes-Dericks, G.L. Carboni, et al. (2010)
• Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients — T. Powrózek, D.M. Kowalski, et al. (2014)
• The current state of pemetrexed in ovarian cancer — R.E. Miller, S. Banerjee (2013)
• Enhanced apoptosis by pemetrexed and simvastatin in malignant mesothelioma and lung cancer cells by reactive oxygen species-dependent mitochondrial dysfunction and Bim induction — K.E. Hwang, Y.S. Kim, et al. (2014)

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