QIMR Berghofer

Blockade of PDGFRß circumvents resistance to MEK-JAK inhibition via intratumoral CD8 + T-cells infiltration in triple-negative breast cancer.


BACKGROUND: Despite the increasing progress in targeted and immune based-directed therapies for other solid organ malignancies, currently there is no targeted therapy available for TNBCs. A number of mechanisms have been reported both in pre-clinical and clinical settings that involve inherent, acquired and adaptive resistance to small molecule inhibitors. Here, we demonstrated a novel resistance mechanism in TNBC cells mediated by PDGFRß in response to JAK2 inhibition. METHODS: Multiple in vitro (subG1, western blotting, immunofluorescence, RT-PCR, Immunoprecipitation), in vivo and publically available datasets were used. RESULTS: We showed that TNBC cells exposed to MEK1/2-JAK2 inhibitors exhibit resistant colonies in anchorage-independent growth assays. Moreover, cells treated with various small molecule inhibitors including JAK2 promote PDGFRß upregulation. Using publically available databases, we showed that patients expressing high PDGFRß or its ligand PDGFB exhibit poor relapse-free survival upon chemotherapeutic treatment. Mechanistically we found that JAK2 expression controls steady state levels of PDGFRß. Thus, co-blockade of PDGFRß with JAK2 and MEK1/2 inhibitors completely eradicated resistant colonies in vitro. We found that triple-combined treatment had a significant impact on CD44 + /CD24 - stem-cell-like cells. Likewise, we found a significant tumor growth inhibition in vivo through intratumoral CD8 + T cells infiltration in a manner that is reversed by anti-CD8 antibody treatment. CONCLUSION: These findings reveal a novel regulatory role of JAK2-mediated PDGFRß proteolysis and provide an example of a PDGFRß-mediated resistance mechanism upon specific target inhibition in TNBC.

Authors Kalimutho, Murugan; Sinha, Debottam; Mittal, Deepak; Srihari, Sriganesh; Nanayakkara, Devathri; Shafique, Shagufta; Raninga, Prahlad; Nag, Purba; Parsons, Kate; Khanna, Kum Kum
Journal Journal of experimental & clinical cancer research : CR
Pages 85
Volume 38
Date 1/02/2019
Grant ID 1017028
Funding Body NH&MRC
URL http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1186/s13046-019-1075-5