| Autor: |
Zhang, Haibo, Read, Abigail, Cataisson, Christophe, Yang, Howard H., Lee, Wei-Chun, Turk, Benjamin E., Yuspa, Stuart H., Luo, Ji |
| Předmět: |
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| Zdroj: |
Science Signaling; 5/14/2024, Vol. 17 Issue 836, p1-16, 16p |
| Abstrakt: |
The Ras–mitogen-activated protein kinase (MAPK) pathway is a major target for cancer treatment. To better understand the genetic pathways that modulate cancer cell sensitivity to MAPK pathway inhibitors, we performed a CRISPR knockout screen with MAPK pathway inhibitors on a colorectal cancer (CRC) cell line carrying mutant KRAS. Genetic deletion of the catalytic subunit of protein phosphatase 6 (PP6), encoded by PPP6C, rendered KRAS- and BRAF-mutant CRC and BRAF-mutant melanoma cells more resistant to these inhibitors. In the absence of MAPK pathway inhibition, PPP6C deletion in CRC cells decreased cell proliferation in two-dimensional (2D) adherent cultures but accelerated the growth of tumor spheroids in 3D culture and tumor xenografts in vivo. PPP6C deletion enhanced the activation of nuclear factor κB (NF-κB) signaling in CRC and melanoma cells and circumvented the cell cycle arrest and decreased cyclin D1 abundance induced by MAPK pathway blockade in CRC cells. Inhibiting NF-κB activity by genetic and pharmacological means restored the sensitivity of PPP6C-deficient cells to MAPK pathway inhibition in CRC and melanoma cells in vitro and in CRC cells in vivo. Furthermore, a R264 point mutation in PPP6C conferred loss of function in CRC cells, phenocopying the enhanced NF-κB activation and resistance to MAPK pathway inhibition observed for PPP6C deletion. These findings demonstrate that PP6 constrains the growth of KRAS- and BRAF-mutant cancer cells, implicates the PP6–NF-κB axis as a modulator of MAPK pathway output, and presents a rationale for cotargeting the NF-κB pathway in PPP6C-mutant cancer cells. Editor's summary: Inhibitors of the Ras-MAPK pathway are used to treat cancers carrying RAS and BRAF mutations. Zhang et al. performed a CRISPR-based screen to find modulators of the MAPK pathway and found that protein phosphatase 6 (PP6) increased sensitivity to MAPK pathway inhibitors. Deletion of the catalytic subunit of PP6 promoted the growth of KRAS- and BRAF-mutant cells in spheroid cultures and in mice in an NF-κB–dependent manner and increased their resistance to MAPK pathway inhibitors. These findings indicate that PP6 contributes to MAPK sensitivity in KRAS- and BRAF-mutant cells and suggest that the NF-κB pathway may be cotargeted in PP6C-mutant cells. —Amy E. Baek [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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