ERBB1/EGFR and JAK3 Tyrosine Kinases as Potential Therapeutic Targets in High-Risk Multiple Myeloma

Abstract

Our main objective was to identify abundantly expressed tyrosine kinases in multiple myeloma (MM) as potential therapeutic targets. We first compared the transcriptomes of malignant plasma cells from newly diagnosed MM patients who were risk-categorized based on the patient-specific EMC-92/SKY-92 gene expression signature values vs. normal plasma cells from healthy volunteers using archived datasets from the HOVON65/GMMG-HD4 randomized Phase 3 study evaluating the clinical efficacy of bortezomib induction/maintenance versus classic cytotoxic drugs and thalidomide maintenance. In particular, ERBB1/EGFR was significantly overexpressed in MM cells in comparison to normal control plasma cells, and it was differentially overexpressed in MM cells from high-risk patients. Amplified expression of EGFR/ERBB1 mRNA in MM cells was positively correlated with increased expression levels of mRNAs for several DNA binding proteins and transcription factors with known upregulating activity on EGFR/ERBB1 gene expression. MM patients with the highest ERBB1/EGFR expression level had significantly shorter PFS and OS times than patients with the lowest ERBB1/EGFR expression level. High expression levels of EGFR/ERBB1 were associated with significantly increased hazard ratios for unfavorable PFS and OS outcomes in both univariate and multivariate Cox proportional hazards models. The impact of high EGFR/ERBB1 expression on the PFS and OS outcomes remained significant even after accounting for the prognostic effects of other covariates. These results regarding the prognostic effect of EGFR/ERBB1 expression were validated using the MMRF-CoMMpass RNAseq dataset generated in patients treated with more recently applied drug combinations included in contemporary induction regimens. Our findings provide new insights regarding the molecular mechanism and potential clinical significance of upregulated EGFR/ERBB1 expression in MM.

Upregulated Expression of ErbB1 in Diffuse Large B-Cell Lymphoma as a Predictor of Poor Overall Survival Outcome

“…A normalization procedure performed at the level of each probeset enabled us to compare the mRNA expression of specific probesets in primary DLBCL cells vs. normal BLC populations from healthy volunteer donors. Batch normalized Affymetrix CEL files employing Aroma Affymetrix statistical packages ran in R quantified log 2 -scaled probeset-level PM signals using the method of Robust Multiarray Analysis as previously described [ 22 ].…”

“…A hierarchical clustering technique organized probeset-level and patient-level mRNA profiles to visualize similarly expressing samples and probesets by clustering them together using the average distance metric to the mRNA expression profiles as previously described in detail [ 22 ].…”

“…Additionally, ERBB1 pathway activation by AREG in MM-derived exosomes has been reported to trigger osteoclastogenesis, and ERBB1 pathway inhibitors are cytotoxic to MM cells [ 20 , 21 ]. Our recent studies demonstrated that ERBB1 expression was upregulated in MM cells, and higher levels of ERBB1 were associated with poor treatment outcomes and survival in newly diagnosed MM [ 22 ].…”

Quinazoline‐chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in‐silico studies of potential anticancer activity against multiple myeloma

“…[ 40 ] Protein tyrosine kinases (PTKs) are essential for normal lymphohematopoietic and have been implicated as oncoproteins in the development of β‐lineage lymphoid malignancies, including leukemias, lymphomas, and MM. [ 41–45 ] Also, the induction of apoptosis in human cancer cells can be achieved by inhibiting several PTKs. [ 46–48 ] Surprisingly, MM patients with the highest EGFR expression had the lowest survival rates.…”

“…[40] Protein tyrosine kinases (PTKs) are essential for normal lymphohematopoietic and have been implicated as oncoproteins in the development of β-lineage lymphoid malignancies, including leukemias, lymphomas, and MM. [41][42][43][44][45] Also, the induction of apoptosis in human cancer cells can F I G U R E 1 Histone deacetylase inhibitors and their common pharmacophore structure. SAHA, suberoylanilide hydroxamic acid; ZBG, zinc-binding group.…”