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KSR induces RAS-independent MAPK pathway activation and modulates the efficacy of KRAS inhibitors

Guillem Paniagua1, Harrys K C Jacob1, Oksana Brehey1

  • 1Experimental Oncology, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.

Molecular Oncology
|March 21, 2022
PubMed

Insights

Kinase suppressor of RAS (KSR) proteins activate the MAPK pathway and cell proliferation independently of RAS. KSR proteins function upstream of RAF, requiring RAF dimerization for signaling and impacting cancer drug response.

Area of Science:

  • Cellular signaling
  • Cancer biology
  • Molecular mechanisms

Background:

  • Kinase suppressor of RAS (KSR) proteins (KSR1 and KSR2) are traditionally viewed as scaffolding proteins essential for mitogen-activated protein kinase (MAPK) pathway signaling.
  • Emerging evidence indicates a more intricate role for KSR proteins within the MAPK pathway.

Purpose of the Study:

  • To elucidate the precise role of KSR1 and KSR2 in MAPK pathway activation and cell proliferation.
  • To investigate the interaction of KSR proteins with RAF and their localization.
  • To assess the impact of KSR protein expression on cancer cell response to targeted therapies.

Main Methods:

  • Ectopic expression of KSR1 and KSR2 in cell lines.
  • Analysis of MAPK pathway activation and cell proliferation.
  • Investigating KSR dimerization with RAF family members.
  • Assessing protein translocation to the cell membrane.
  • Site-directed mutagenesis of KSR1 (Asp-Phe-Gly motif).
  • Evaluating the effect of KSR1 expression on sotorasib sensitivity in human cancer cell lines.

Main Results:

  • Ectopic KSR1 or KSR2 expression activates the MAPK pathway and induces cell proliferation, even without RAS proteins.
  • KSR protein expression alone does not induce proliferation without RAF or MAPK-ERK kinase, positioning KSR upstream of RAF.
  • KSR1 requires dimerization with a RAF protein, leading to RAF translocation to the cell membrane for proliferation.
  • Mutations in the KSR1 ATP-binding motif abolish proliferation induction.
  • Elevated KSR1 levels reduce cancer cell sensitivity to the KRASG12C inhibitor sotorasib.

Conclusions:

  • KSR proteins are potent activators of the MAPK pathway, acting upstream of RAF and requiring RAF dimerization for signaling.
  • KSR's role extends beyond scaffolding, influencing cell proliferation and potentially mediating resistance to KRAS-targeted therapies.
  • Increased KSR expression may render tumor cells less reliant on KRAS signaling, suggesting KSR as a potential therapeutic target or biomarker.
Keywords:
ATP bindingKRASG12CMAPK pathwayRAS-independent proliferationresistancesotorasib

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