Our data support a role for NFKBIA in the suppression of glioblastoma tumors. The presence of NFKBIA deletions in some glioblastoma cancer stem cells suggests that such deletions can emerge early in the pathogenesis of glioblastoma. Our data show that loss of NFKBIA can also be associated with disease progression and tumor recurrence.
The general, albeit not absolute, mutual exclusivity of NFKBIA
deletion and EGFR
amplification has been reported in the case of other gene pairs in signaling pathways pertinent to the biologic nature of glioblastomas. For example, a decrease in retinoblastoma pathway signaling is achieved through a mutually exclusive mutation of the tumor-suppressor gene RB1
or deletion of the tumor-suppressor genes CDKN2A
Similarly, mutations in the tumor-suppressor gene TP53
and deletions affecting CDKN2A
, both of which reduce TP53 pathway signaling, appear to be mutually exclusive in glioblastomas.38
The fact that tumors with deletion of NFKBIA
and those with EGFR
amplification have similarly poor outcomes suggests that NFKBIA
deletion can substitute for EGFR
amplification in the pathogenesis of glioblastoma. This finding is consistent with our observation that deletion of NFKBIA
occurs more commonly in nonclassical glioblastomas than in classical glioblastomas, which have EGFR
amplification more often than do nonclassical glioblastomas. Which aberration occurs may depend on the tumor’s cell of origin and its pattern of accumulation of the other genetic lesions that define glioblastoma subtypes.9
We have observed, in a previous study, that glioblastoma cells that do not respond to temozolomide chemotherapy have comparatively low expression of NFKBIA14
and, in this study, that increasing NFKBIA expression in these cells sensitizes them to temozolomide. Our findings, together with research showing the role of NFKBIA as a gatekeeper for EGFR signaling11
and the involvement of EGFR activation in the lack of response of glioblastoma cells to chemotherapy and radiotherapy,39
collectively suggest that NFKBIA-mediated sensitization of glioblastoma cells to temozolomide reflects NFKBIA abrogation of EGFR signaling.
Our observation that NFKBIA status is independently associated with survival in several patient groups supports the importance of NFKBIA as a determinant of glioblastoma behavior, including the response to temozolomide, and suggests that it would be useful to include the gene dosage or expression of NFKBIA in models predicting survival. Our data show that a risk model combining NFKBIA status and MGMT status (currently the best single predictor of response to temozolomide therapy for glioblastomas33
) was strongly associated with the clinical course of the disease. This makes sense mechanistically: concomitant down-regulation of NFKBIA (enhancing the pro-survival effect of NF-κ
B) and up-regulation of MGMT (enhancing the repair of DNA damage) could have a synergistic, positive effect on resistance to therapeutic response and cell death.
Our finding that increased expression of NFKBIA inhibited the malignant behavior of tumors that had amplified EGFR
and normal dosage of NFKBIA
(in addition to tumors with deletions of NFKBIA
) suggests that NFKBIA-stabilizing therapies may be effective against glioblastomas that have alterations of EGFR
. The limited efficacy of molecular therapies targeting EGFR in glioblastomas suggests that the therapeutic effect of EGFR inhibition can be circumvented through cross-coupled signaling from other growth factor receptors that are mutated, amplified, or overexpressed in these tumors, such as PDGFRA, ERBB2,
Because NFKBIA is a major node downstream of such cross-coupled signaling, therapies that stabilize NFKBIA might more effectively restrain oncogenic signaling.