Abstract
Background:
We have previously reported on the putative role of c-MET/ERK-1/2/ELK1/Proteassemblin (POMP) signaling axis in enhancing proteasome assembly and capacity, which in multiple myeloma (MM) treatment may reduce sensitivity to proteasome inhibitors (PIs) such ascarfilzomib orbortezomib [ASH 2014 MeetingAbstr. 274]. The transcription factor ELK1 was found to regulate POMP expression andcarfilzomib resistance via binding to transcription initiation sites of the POMP gene promoter containing two ELK-1 consensus binding sites. Analysis of the Millennium Pharmaceuticals gene expression profile (GEP) database of patients treated withbortezomib in the relapsed and relapsed/refractory settings showed that patients who had higher expression of MUC20 had superior overall survival (OS) and progression free survival (PFS) compared to those who had lower expression. However, similar outcome was not assessed for other downstream members of this signaling cascade, including the transcription factor ELK1.
Methods:
We performed statistical analysis on patient and GEP data bases downloaded from the Multiple Myeloma Research Foundation Researcher Gateway website (http://research.themmrf.org),with the objective ofassessing the effects of ELK1 gene expression (gene probe ENSG00000126767) on the OS and PFSin453 patients who had data available on both demographic and clinical characteristics, as well as GEP collected during their first-line therapy.Patients were characterized by clinical variables including age, gender, race, ethnicity, therapy received and international staging system (ISS).ELK1 gene expression was dichotomized into two groups:greater than or equal to median, or less than median expression of the ELK1 gene. The distributions of OS and PFS were estimated by the Kaplan-Meier method.
Results:
The median patient age was 64 years (range, 27- 93), and 60% of them were male. Of 453 patients, 350 (77%) were Caucasian, 75 (17%) African-American and 11 (2%) Asian. 420 (93%) were receiving first line of therapy, while 27 (6%) and 4 (1%) were receiving second or third line therapies, respectively. Two hundred and thirty nine (53%) patients received combinedbortezomib/immunomodulatory (IMiD) based therapy, 142 (31%) receivedbortezomib-based, and a further 33 (7%) receivedIMiD-based therapy alone, while 24 (5%) patients received combinedcarfilzomib/IMiD based therapy. One hundred and forty seven (33%) patients were ISS stage I,162 (37%) stage II, and 133 (30%) stage III. There were 39 deaths, of which 19 (49%) were due to disease progression. Patents who were greater than or equal to 64 years old had inferior OS compared to those less than 64 years of age (p=0.0266), patients who had ISS stage I or II had superior OS compared to those with stage III (p=0.00983), and after adjusting for stage III, patients who had less than median ELK1 gene expression had superior OS compared to those with greater than or equal to median ELK1 gene expression (Figure 1., p=0.00309). PFS was not affected.
Conclusions: Our data continue to support a role for signaling through the c-MET/ERK-1/2/ELK1/POMP axis in enhancing proteasome assembly and capacity, thereby reducing sensitivity to proteasome inhibitors likecarfilzomib orbortezomib in MM. As such, the use of drugs suppressing c-MET signaling in early phase trial design, particularly in combination with other PIs, remains a potentially attractive strategy to overcome resistance to PIs in the clinic.
The overall survival curve for the patients who had less than median ELK1 gene expression and greater than or equal to median ELK1 gene expression.
The overall survival curve for the patients who had less than median ELK1 gene expression and greater than or equal to median ELK1 gene expression.
No relevant conflicts of interest to declare.
