MSH6 inactivation and emergent temozolomide resistance in human glioblastomas.

Glioblastomas are the most commonly diagnosed primary human brain tumors. Unfortunately, these cancers are almost uniformly fatal; regardless of treatment, median survival is less than 2 years after diagnosis.20 Current standard of care is maximal safe surgical resection followed by combined adjuvant radiation therapy and chemotherapy with the methylating alkylator agent temozolomide. Nonetheless, virtually all patients experience tumor regrowth, which is resistant to prior therapies and ultimately leads to the patient’s death. We review recent large-scale molecular genetic studies of glioblastoma treatment resistance. To identify genetic alterations driving the growth and treatment resistance of glioblastoma, large-scale genomic analysis in malignant gliomas was pursued as part of an international collaborative cancer genome sequencing effort.14 Unexpectedly, two glioblastomas, which were both recurrent tumors from patients who had received temozolomide, had large numbers of somatic mutations across many genes. By comparison, treatment-naı̈ve tumors had orders-of-magnitude fewer mutations. The overall pattern of mutation suggested that a mutator phenotype had arisen in the recurrent cases during treatment. Thereafter, somatic inactivating mutations of the human DNA mismatch repair (MMR) gene MSH6 were discovered in these recurrences, but not in any untreated tumors.16 Across a large number of well-characterized clinical samples, loss of the MSH6 protein occurred only in the subset of recurrent glioblastomas that had been treated with temozolomide and was associated with progressive growth of these tumors while they were under temozolomide treatment.6 These studies represented the first identification of somatic inactivation of MSH6 in recurrent human tumors of any tissue type and linkage of this loss with therapeutic resistance. Interestingly, these observations in human cancers mirrored prior comprehensive screening analyses identifying MMR pathway inactivation mediating alkylator resistance in vitro.3,11–13,18,23 Taken together, this work has led to the proposal that MMR inactivation can serve as an in vivo route of emergent temozolomide chemoresistance in patients with glioblastoma. By selectively targeting this molecular pathway of temozolomide treatment escape with newer agents and modalities such as poly (adenosine 5 -diphosphate-ribose) polymerase inhibitors, local drug delivery polymers, or immunotherapeutics, there is hope for the improved design of combination therapeutic regimens.