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Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells

Hiu-Fung Yuen1, Olga Abramczyk, Grant Montgomery

  • 1Centre for Cancer Research and Cell Biology (CCRCB), Queen’s University Belfast, Belfast, U.K.

Bioscience Reports
|June 7, 2012
PubMed

Insights

Feedback between PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways is crucial for cancer therapy. This feedback is cell-specific, depending on K-Ras mutations or c-Met amplification, identifying key biomarkers for patient response.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • Targeting phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) and Ras/mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) pathways is a long-standing cancer therapy strategy with limited success.
  • Patient responses to these inhibitors vary significantly due to genetic mutations causing drug insensitivity and compensatory mechanisms.
  • Understanding pathway feedback in relation to specific mutations is vital for identifying predictive biomarkers for patient response.

Purpose of the Study:

  • To investigate the cell-specific feedback mechanisms between the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways in cancer.
  • To determine the role of K-Ras mutations and c-Met overexpression in mediating this feedback.
  • To identify potential biomarkers for predicting patient response to PI3K and MEK inhibitors.

Main Methods:

  • Utilized specific inhibitors: PD184352 (MEK inhibitor) and PI103 (PI3K inhibitor).
  • Examined differential signaling and apoptotic responses in cancer cell lines with varying genetic backgrounds (K-Ras mutations, c-Met amplification, wild-type).
  • Investigated the effect of okadaic acid (OA), a protein phosphatase inhibitor, on pathway feedback in wild-type cells.

Main Results:

  • Feedback from the PI3K/Akt/mTORC1 to the Ras/MEK/ERK pathway was observed exclusively in cancer cells with K-Ras activating mutations or c-Met amplification, not in wild-type counterparts.
  • Cell lines displayed distinct signaling and apoptotic outcomes when treated with PD184352 and PI103, highlighting pathway crosstalk.
  • Inhibition of protein phosphatase activity using OA restored PI103-mediated feedback in wild-type cells, suggesting a role for endogenous phosphatases.

Conclusions:

  • A novel feedback mechanism exists between the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways, specific to K-Ras mutant and c-Met amplified cancer cells.
  • This feedback loop appears to involve the inhibition of specific endogenous phosphatase activity.
  • Monitoring K-Ras and c-Met status are critical biomarkers for predicting the efficacy of PI103 and other PI3K/Akt inhibitors in cancer therapy.

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