Journal
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume 38, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13046-019-1075-5
Keywords
TNBC; PDGFR beta; JAK2; Resistance; CD8(+) T cell
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Funding
- National Health & Medical Research Council (NH&MRC) Program Grant [1017028]
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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 PDGFR 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 PDGFR beta upregulation. Using publically available databases, we showed that patients expressing high PDGFR beta or its ligand PDGFB exhibit poor relapse-free survival upon chemotherapeutic treatment. Mechanistically we found that JAK2 expression controls steady state levels of PDGFR beta. Thus, co-blockade of PDGFR beta with JAK2 and MEK1/2 inhibitors completely eradicated resistant colonies in vitro. We found that triple-combined treatment had asignificant impact on CD44(+)/CD24(-) stem-cell-like cells. Likewise, we found a significant tumor growth inhibition in vivo through intratumoral CD8(+) T cells infiltrationin a manner that is reversed by anti-CD8 antibody treatment. Conclusion: These findings reveal a novel regulatory role of JAK2-mediated PDGFR beta proteolysis and provide an example of a PDGFR beta-mediated resistance mechanism upon specific target inhibition in TNBC.
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