Abstract
Glioblastoma (GBM) is an aggressive and incurable tumor of the brain with limited treatment options. Current first-line standard of care is the DNA alkylating agent temozolomide (TMZ), but this treatment strategy adds only ~4 months to median survival due to the rapid development of resistance. While some mechanisms of TMZ resistance have been identified, they are not fully understood. There are few effective strategies to manage therapy resistant GBM, and we lack diverse preclinical models of acquired TMZ resistance in which to test therapeutic strategies on TMZ resistant GBM. In this study, we create and characterize two new GBM cell lines resistant to TMZ in vitro, based on the 8MGBA and 42MGBA cell lines. Analysis of the TMZ resistant (TMZres) variants in conjunction with their parental, sensitive cell lines shows that acquisition of TMZ resistance is accompanied by broad phenotypic changes, including increased proliferation, migration, chromosomal aberrations, and secretion of cytosolic lipids. Importantly, each TMZ resistant model captures a different facet of the “go” (8MGBA-TMZres) or “grow” (42MGBA-TMZres) hypothesis of GBM behavior. These in vitro model systems will be important additions to the available tools for investigators seeking to define molecular mechanisms of acquired TMZ resistance.
Highlights
Cell line models have been invaluable in elucidating the molecular mechanisms behind the uncontrolled growth of cancer cells
The shape of the SubG1 curves differed between the two cell lines – 8MGBA-WT cells treated with TMZ showed a defined SubG1 peak typically associated with apoptosis, while 42MGBA-WT cells did not (Supp Fig. 1a,b)
This was corroborated by immunoblotting for cleaved poly (ADP-ribose) polymerase (PARP), which was observed in 8MGBA-WT but not 42MGBA-WT cells (Fig. 1g,h)
Summary
Cell line models have been invaluable in elucidating the molecular mechanisms behind the uncontrolled growth of cancer cells. As the cell lines acquired resistance to TMZ both cell lines gained expression of MGMT, showed an increase in nuclear size and chromosome number, and an increase of early endosomes and extracellular lipids. As they differed in their growth and migratory capacity, these cell lines may give us insight into the “go or grow” model for GBM recurrence[13]. The 8MBGA-TMZ resistant cell line had an increase in migration, encompassing the “grow” aspect of resistance These models will be useful tools for the field to better define essential drug resistance mechanisms in GBM. These two TMZ-resistant (TMZres) models from both a male and female patient have evolved distinct resistant phenotypes and serve as valuable resources to investigate the heterogeneity of TMZ-resistant GBM
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