Abstract
KRAS is one of the most important proto-oncogenes. Its mutations occur in almost all tumor types, and KRAS mutant cancer is still lack of effective therapy. Prenyl-binding protein phosphodiesterase-δ (PDEδ) is required for the plasma membrane association and subsequent activation of KRAS oncogenic signaling. Recently, targeting PDEδ has provided new promise for KRAS mutant tumors. However, the therapeutic potential of PDEδ inhibition remains obscure. In this study, we explored how PDEδ inhibition was responded in KRAS mutant cancer cells, and identified KRAS mutant subset responsive to PDEδ inhibition. We first performed siRNA screen of KRAS growth dependency of a small panel of human cancer lines, and identified a subset of KRAS mutant cancer cells that were highly dependent on KRAS signaling. Among these cells, only a fraction of KRAS-dependent cells responded to PDEδ depletion, though KRAS plasma membrane association was effectively impaired. We revealed that the persistent RAF/MEK/ERK signaling seemed responsible for the lack of response to PDEδ depletion. A kinase array further identified that the feedback activation of EPH receptor A2 (EPHA2) accounted for the compensatory activation of RAF/MEK/ERK signaling in these cells. Simultaneous inhibition of EPHA2 and PDEδ led to the growth inhibition of KRAS mutant cancer cells. Together, this study gains a better understanding of PDEδ-targeted therapeutic strategy and suggests the combined inhibition of EPHA2 and PDEδ as a potential therapy for KRAS mutant cancer.
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16 January 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41401-023-01208-1
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 81821005), and the Strategic Priority Research Program of the Chinese Academy of Sciences (Nos XDA12020345 and XDA12020230).
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MH conceived the whole project; BX and MH initiated the project; MYG and JD provided supervision; YHC performed the research and analyzed the data; HL performed the experiments in the initial stage of the project; XMW, NS, and ST provided technique assistance; MH and YHC wrote the paper. All authors approved the final version of the paper.
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Chen, Yh., Lv, H., Shen, N. et al. EPHA2 feedback activation limits the response to PDEδ inhibition in KRAS-dependent cancer cells. Acta Pharmacol Sin 41, 270–277 (2020). https://doi.org/10.1038/s41401-019-0268-y
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DOI: https://doi.org/10.1038/s41401-019-0268-y
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