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Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines

Susann Weißbach1, Sofia Catalina Heredia-Guerrero1, Stefanie Barnsteiner1

  • 1Institute of Pathology, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany.

Cancers
|February 22, 2020
PubMed

Insights

KRAS mutations are common in multiple myeloma (MM) but do not impact patient survival. However, these KRAS variants can activate key signaling pathways involved in cell survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Approximately 20% of multiple myeloma (MM) cases harbor KRAS point mutations.
  • The prognostic significance of KRAS mutations in MM, particularly with novel agents, remains unclear.
  • KRAS is a challenging therapeutic target, though mutation-specific inhibitors are emerging.

Purpose of the Study:

  • To investigate the impact of KRAS mutations on survival in newly diagnosed MM patients treated with novel agents.
  • To functionally characterize specific KRAS mutations (p.G12A, p.A146T, p.A146V) and their effect on MM cell signaling pathways.

Main Methods:

  • Deep sequencing of KRAS coding regions in 80 newly diagnosed MM patients.
  • Analysis of patient survival data following uniform VCD-induction therapy and stem cell transplantation.
  • Overexpression of wild-type (WT) and mutant KRAS (p.G12A, p.A146T, p.A146V) in cell lines to assess signaling pathway activation (MEK/ERK, PI3K/AKT).

Main Results:

  • No correlation was found between KRAS mutations and patient survival in this cohort.
  • All investigated KRAS mutants demonstrated the potential to activate the MEK/ERK signaling pathway.
  • KRAS mutants sustained PI3K/AKT signaling in MM cells.

Conclusions:

  • KRAS mutations do not appear to influence survival outcomes in newly diagnosed multiple myeloma patients treated with current novel agents.
  • Despite lacking prognostic impact, KRAS mutations can modulate critical cell signaling pathways, suggesting potential therapeutic avenues.
Keywords:
AKT-signalingKRASMEK/ERK-signalingamplicon sequencingmultiple myeloma

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