Targeting PYK2 mediates microenvironment-specific cell death in multiple myeloma
Authors: L Mathews
J E Ring
I Rosado-Lopez
T Nguyen
A R MacLeod
L Nong
M B Meads
J M Koomen
B Fang
W Matsui
J A Pachter
L A Hazlehurst
K H Shain
J Gemmer
Journal: Oncogene (2016)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Multiple myeloma; bone marrow microenvironment; survival signaling; β1 integrin; interleukin-6
Affiliations: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Proteomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Verastem, Inc., Needham, Massachusetts, USA., Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA., ISIS Pharmaceuticals, Carlsbad, CA, USA., Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Abstract:  Multiple myeloma (MM) remains an incurable malignancy due, in part, to the influence of the bone marrow microenvironment on survival and drug response. Identification of microenvironment-specific survival signaling determinants is critical for the rational design of therapy and elimination of MM. Previously, we have shown that collaborative signaling between β1 integrin-mediated adhesion to fibronectin and interleukin-6 confers a more malignant phenotype via amplification of signal transducer and activator of transcription 3 (STAT3) activation. Further characterization of the events modulated under these conditions with quantitative phosphotyrosine profiling identified 193 differentially phosphorylated peptides. Seventy-seven phosphorylations were upregulated upon adhesion, including PYK2/FAK2, Paxillin, CASL and p130CAS consistent with focal adhesion (FA) formation. We hypothesized that the collaborative signaling between β1 integrin and gp130 (IL-6 beta receptor, IL-6 signal transducer) was mediated by FA formation and proline-rich tyrosine kinase 2 (PYK2) activity. Both pharmacological and molecular targeting of PYK2 attenuated the amplification of STAT3 phosphorylation under co-stimulatory conditions. Co-culture of MM cells with patient bone marrow stromal cells (BMSC) showed similar β1 integrin-specific enhancement of PYK2 and STAT3 signaling. Molecular and pharmacological targeting of PYK2 specifically induced cell death and reduced clonogenic growth in BMSC-adherent myeloma cell lines, aldehyde dehydrogenase-positive MM cancer stem cells and patient specimens. Finally, PYK2 inhibition similarly attenuated MM progression in vivo. These data identify a novel PYK2-mediated survival pathway in MM cells and MM cancer stem cells within the context of microenvironmental cues, providing preclinical support for the use of the clinical stage FAK/PYK2 inhibitors for treatment of MM, especially in a minimal residual disease setting. 

Retracted: No

PubPeer comments:
 Concerns about possible splices in Figures 6a and 6b. Other readers on Twitter suggest RPMI8226 actin may not have an obvious splice, but agree with the concerns indicated in red on the other two images. *** ![file] *** ![file] *** ![file] , 
 #1 Another look at these figures. ***![file] ,