Blockade of PDGFRβ circumvents resistance to MEK-JAK inhibition via intratumoral CD8+ T-cells infiltration in triple-negative breast cancer
Autor: | Sriganesh Srihari, Kate Parsons, Purba Nag, Kum Kum Khanna, Prahlad V. Raninga, Devathri Nanayakkara, Deepak Mittal, Shagufta Shafique, Murugan Kalimutho, Debottam Sinha |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment MAP Kinase Kinase 2 PDGFRβ Resistance MAP Kinase Kinase 1 Triple Negative Breast Neoplasms CD8-Positive T-Lymphocytes lcsh:RC254-282 Targeted therapy Receptor Platelet-Derived Growth Factor beta 03 medical and health sciences Lymphocytes Tumor-Infiltrating 0302 clinical medicine Immune system In vivo medicine Humans Janus Kinase Inhibitors Cytotoxic T cell Triple-negative breast cancer PDGFB biology Chemistry Research CD44 Janus Kinase 2 lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 3. Good health 030104 developmental biology Oncology JAK2 Drug Resistance Neoplasm 030220 oncology & carcinogenesis biology.protein Cancer research Female CD8+ T cell TNBC CD8 |
Zdroj: | Journal of Experimental & Clinical Cancer Research, Vol 38, Iss 1, Pp 1-18 (2019) Journal of Experimental & Clinical Cancer Research : CR |
ISSN: | 1756-9966 |
Popis: | 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 PDGFRβ 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 PDGFRβ upregulation. Using publically available databases, we showed that patients expressing high PDGFRβ or its ligand PDGFB exhibit poor relapse-free survival upon chemotherapeutic treatment. Mechanistically we found that JAK2 expression controls steady state levels of PDGFRβ. Thus, co-blockade of PDGFRβ 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 PDGFRβ proteolysis and provide an example of a PDGFRβ-mediated resistance mechanism upon specific target inhibition in TNBC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1075-5) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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