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Targeting PAK1 is effective against cutaneous squamous cell carcinoma in a syngenic mouse model
Kazuhiro Okumura1, Takao Morinaga2, Megumi Saito1
1Division of Experimental Animal Research, Cancer Genome Center, Chiba Cancer Center Research Institute, Chiba, Japan.
Abstract:
By taking advantage of forward genetic analysis in mice, we have demonstrated that Pak1 plays a crucial role during DMBA/TPA skin carcinogenesis. Although Pak1 has been considered to promote cancer development, its overall function remains poorly understood. To clarify the functional significance of Pak1 in detail, we sought to evaluate the possible effect of an allosteric inhibitor against PAK1 (NVS-PAK1-1) on a syngeneic mouse model. To this end, we established two cell lines, 9AS1 and 19AS1, derived from DMBA/TPA-induced squamous cell carcinoma (SCC) that engrafted in FVB mice. Based on our present results, NVS-PAK1-1 treatment significantly inhibited the growth of tumors derived from 9AS1 and 19AS1 cells in vitro and in vivo. RNA-sequencing analysis on the engrafted tumors indicates that NVS-PAK1-1 markedly potentiates the epidermal cell differentiation and enhances the immune response in the engrafted tumors. Consistent with these observations, we found an expansion of Pan-keratin-positive regions and potentially elevated infiltration of CD8-positive immune cells in NVS-PAK1-1-treated tumors as examined by immunohistochemical analyses. Together, our present findings strongly suggest that PAK1 is tightly linked to the development of SCC, and that its inhibition is a promising therapeutic strategy against SCC.
Insights
Pak1 inhibition effectively suppressed squamous cell carcinoma (SCC) growth in mice. This treatment also enhanced epidermal cell differentiation and boosted the immune response, suggesting PAK1 inhibition as a promising SCC therapy.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Pak1 (p21-activated kinase 1) is implicated in cancer development, but its precise role in skin carcinogenesis is not fully understood.
- Forward genetic analysis in mice provides a powerful tool to investigate gene functions in complex biological processes like cancer.
Purpose of the Study:
- To investigate the role of Pak1 in DMBA/TPA-induced skin carcinogenesis.
- To evaluate the therapeutic potential of an allosteric PAK1 inhibitor, NVS-PAK1-1, in a syngeneic mouse model of squamous cell carcinoma (SCC).
Main Methods:
- Establishment of two SCC cell lines (9AS1 and 19AS1) from DMBA/TPA-induced tumors in FVB mice.
- Treatment of these cell lines and derived tumors with NVS-PAK1-1 in vitro and in vivo.
- RNA-sequencing and immunohistochemical analyses of tumors to assess molecular and cellular changes.
Main Results:
- NVS-PAK1-1 treatment significantly inhibited the growth of SCC tumors derived from 9AS1 and 19AS1 cells.
- RNA-seq revealed that NVS-PAK1-1 potentiated epidermal cell differentiation and enhanced the immune response within tumors.
- Immunohistochemistry confirmed increased Pan-keratin expression and elevated CD8+ T cell infiltration in treated tumors.
Conclusions:
- Pak1 is critically involved in the development of DMBA/TPA-induced squamous cell carcinoma.
- Inhibition of Pak1 using NVS-PAK1-1 demonstrates therapeutic efficacy by promoting differentiation and augmenting anti-tumor immunity.
- Targeting Pak1 represents a promising therapeutic strategy for SCC treatment.
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