The Role of PDGFR-β Activation in Acquired Resistance to IGF-1R Blockade in Preclinical Models of Rhabdomyosarcoma

Heske, Christine M.; Yeung, Choh; Mendoza, Arnulfo; Baumgart, Joshua T.; Edessa, Leah D.; Wan, Xiaolin; Helman, Lee J.

doi:10.1016/j.tranon.2016.09.002

Cited by 12 publications

(8 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The in vivo study revealed that siRNA inhibition of PDGFR-β resulted in a significant reduction in cell growth and invasion of CRC cell lines (P<0.05). Furthermore, PDGFR has recently been reported as a possible new therapeutic target in several solid tumors, such as breast cancer, gastrointestinal stromal tumor, lung cancer and rhabdomyosarcoma (8,(18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

Platelet‑derived growth factor receptor‑β gene expression relates to recurrence in colorectal cancer

et al. 2018

View full text Add to dashboard Cite

Platelet‑derived growth factor receptor‑β (PDGFR‑β) in epithelial tumors is mainly expressed by stromal cells. High expression of PDGFR‑β has been related to poor prognosis in several cancers, however its significance in colorectal cancer (CRC) remains unknown. The present study aimed to clarify the prognostic impact of PDGFR‑β in CRC patients. The study included 194 patients who underwent surgery for CRC. PDGFR‑β expression was examined by real‑time reverse transcription‑polymerase chain reaction and immunohistochemistry and the expression levels were correlated with various clinical parameters. The biological significance was evaluated by knockdown experiments in CRC cell lines and the specific PDGFR inhibitor, crenolanib. PDGFR‑β mRNA and protein expression levels were positively correlated with each other. Low PDGFR‑β expression was associated with significantly better disease‑free survival after curative surgical resection, than high PDGFR‑β expression, according to univariate and multivariate analyses. The assessment of PDGFR‑β knockdown in two cell lines revealed that small interfering RNA (siRNA) inhibition resulted in statistically significant reductions in cell growth and invasion. PDGFR inhibitor suppressed CRC cell proliferation in vitro in a dose‑dependent manner. In conclusion, PDGFR‑β expression was a risk factor for recurrence in patients with CRC and PDGFR inhibitor may be a useful therapeutic agent for CRC.

show abstract

Section: Discussionmentioning

confidence: 99%

Platelet‑derived growth factor receptor‑β gene expression relates to recurrence in colorectal cancer

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Co-targeting IR/IGF1R and PDGFR decreased the number of resistant clones in vitro . The enhanced growth inhibition was observed in rhabdomyosarcoma cell lines when cells were treated with dual IGF-1R and PDGFR-β agents in vitro [ 261 ]. Furthermore, PDGFR tyrosine phosphorylation may be inhibited by Compound C resulting in decreased proliferation of A172 glioblastoma cells [ 262 ].…”

Section: Other Targets and Inhibitorsmentioning

confidence: 99%

Antiplatelet agents for cancer treatment: a real perspective or just an echo from the past?

Wojtukiewicz

Hempel²,

Sierko

et al. 2017

Cancer Metastasis Rev

View full text Add to dashboard Cite

The association between coagulation and cancer development has been observed for centuries. However, the connection between inflammation and malignancy is also well-recognized. The plethora of evidence indicates that among multiple hemostasis components, platelets play major roles in cancer progression by providing surface and granular contents for several interactions as well as behaving like immune cells. Therefore, the anticancer potential of anti-platelet therapy has been intensively investigated for many years. Anti-platelet agents may prevent cancer, decrease tumor growth, and metastatic potential, as well as improve survival of cancer patients. On the other hand, there are suggestions that antiplatelet treatment may promote solid tumor development in a phenomenon described as “cancers follow bleeding.” The controversies around antiplatelet agents justify insight into the subject to establish what, if any, role platelet-directed therapy has in the continuum of anticancer management.

show abstract

“…Historically, PDGFRβ transcript expression is well known to be activated by many stimuli to promote targeted therapy-mediated resistance in various cancers [37, 40, 54–56]. One pathway implicated in PDGFRβ r egulation is MYC, a transcriptional repressor of PDGFRβ , hence blocking ERK1/2-dependent MYC signaling induces expression and activation of PDGFRβ in breast cancer [37].…”

Section: Discussionmentioning

confidence: 99%

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

Kalimutho

Sinha

Mittal

et al. 2019

J Exp Clin Cancer Res

View full text Add to dashboard Cite

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.

show abstract

The Role of PDGFR-β Activation in Acquired Resistance to IGF-1R Blockade in Preclinical Models of Rhabdomyosarcoma

Cited by 12 publications

References 19 publications

Platelet‑derived growth factor receptor‑β gene expression relates to recurrence in colorectal cancer

Platelet‑derived growth factor receptor‑β gene expression relates to recurrence in colorectal cancer

Antiplatelet agents for cancer treatment: a real perspective or just an echo from the past?

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

Contact Info

Product

Resources

About