PDE4D targeting enhances anti-tumor effects of sorafenib in clear cell renal cell carcinoma and attenuates MAPK/ERK signaling in a CRAF-dependent manner

• Published in: Translational oncology Vol. 19; p. 101377
• Main Authors: Cao, Minghua, Nawalaniec, Karol, Ajay, Amrendra K., Luo, Yueming, Moench, Romana, Jin, Yanfei, Xiao, Sheng, Hsiao, Li-Li, Waaga-Gasser, Ana Maria
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2022; Neoplasia Press; Elsevier
• Subjects: cAMP; CRAF; MAPK/ERK pathway; Original Research; Phosphodiesterase 4D; Renal cell carcinoma; Tyrosine kinase inhibitor; KO; Tyrosine kinase inhibitor; PDE4; PKA; CRAF; cAMP; MAPK; ccRCC; TKI; PI3K; Phosphodiesterase 4D; Renal cell carcinoma; sgRNA; MAPK/ERK pathway; ERK
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2022.101377

•PDE4D is the predominant subtype of PDE4 in renal cancer cells.•CRISPR/Cas9-mediated knockout of PDE4D or inhibition by roflumilast reduced the proliferation and colony formation of Caki-1 ccRCC cells, and inhibited MAPK/ERK signaling in a CRAF-dependent manner.•PDE4D targeting enhanced the ability of sorafenib to stunt the survival of Caki-1 cells.•Knockout of PDE4D enhanced sorafenib-mediated induction of apoptosis in Caki-1 cells.•PDE4D targeting may restore negative feedback on MAPK/ERK signaling in tumors with CRAF-dependent ERK activation. Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer and effective treatment regimens are yet to be established. Tyrosine kinase inhibitors (TKI) have widely been used as ccRCC therapeutics, but their efficacy is limited due to accompanying resistance mechanisms. Previous studies have provided substantial evidence for crosstalk between cAMP and the MAPK/ERK signaling pathway. Low levels of intracellular cAMP have been found in several human malignancies and some data suggest that elevation of cAMP expression can be achieved by phosphodiesterase 4 (PDE4) inhibition, resulting in cell growth arrest and/or cell death. The effects of crosstalk between cAMP and the MAPK/ERK pathway on the development progression in ccRCR, however, remain to be fully understood. In this study, we sought to explore the involvement of PDE4 in ccRCC and to assess its potential as a target for therapeutic intervention. We demonstrated that PDE4D is the predominant subtype of PDE4 expressed in healthy and cancerous renal cell lines, particularly in metastatic Caki-1 cells. We generated a CRISPR/Cas9-mediated PDE4D-KO Caki-1 cell model and showed that PDE4D depletion reduced cell proliferation and recovered cAMP expression in these cells. PDE4D-KO and/or PDE4 inhibition with the FDA approved PDE4 inhibitor, roflumilast, also attenuated MAPK/ERK signaling in a CRAF-dependent manner. Most interestingly, we showed that PDE4D-KO enhanced the effectiveness of the TKI, sorafenib, to stunt cell survival. In conclusion, we provide preliminary evidence of PDE4 involvement in ccRCC and suggest a rationale for dual tyrosine kinase/PDE4D targeting in patients with CRAF-dependent MAPK activation.