Unraveling the CDK9/PP2A/ERK Network in Transcriptional Pause Release and Complement Activation in KRAS-mutant Cancers.

ABSTRACT: Selective inhibition of the transcription elongation factor (P-TEFb) complex represents a promising approach in cancer therapy, yet CDK9 inhibitors (CDK9i) are currently limited primarily to certain hematological malignancies. Herein, while initial responses to CDK9-targeted therapies are observed in vitro across various KRAS-mutant cancer types, their efficacy is far from satisfactory in nude mouse xenograft models. Mechanistically, CDK9 inhibition leads to compensatory activation of ERK-MYC signaling, accompanied by the recovery of proto-oncogenes, upregulation of immediate early genes (IEGs), stimulation of the complement C1r-C3-C3a cascade, and induction of tumor immunosuppression. The "paradoxical" regulation of PP2Ac activity involving the CDK9/Src interplay contributes to ERK phosph

SUBMITTER: Wang Y 

PROVIDER: S-EPMC11538672 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature