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


RESULTS
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.
Department of Cancer Research and Molecular Medicine, IKM, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. oluf.roe@ntnu.no
Oluf Dimitri
OD
Røe
Adam
A
Szulkin
Endre
E
Anderssen
Arnar
A
Flatberg
Helmut
H
Sandeck
Tore
T
Amundsen
Sten Even
SE
Erlandsen
Katalin
K
Dobra
Stein Harald
SH
Sundstrøm
D015720:5'-Nucleotidase / Q000378:metabolism; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001706:Biopsy / Q000379:methods; D002448:Cell Adhesion; D015331:Cohort Studies; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D055106:Genome-Wide Association Study; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008654:Mesothelioma / Q000188:drug therapy*; D020411:Oligonucleotide Array Sequence Analysis; D000068437:Pemetrexed; D010984:Platinum / Q000494:pharmacology*; D014057:Tomography, X-Ray Computed / Q000379:methods; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D005971:Glutamates; D000068437:Pemetrexed; D010984:Platinum; D006147:Guanine; D015720:5'-Nucleotidase; C552626:NT5C1A protein, human