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Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from

Katja Närhi1, Ashwini S Nagaraj1, Elina Parri1

  • 1Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

The Journal of Pathology
|February 15, 2018
PubMed

Insights

Precision medicine uses spatial signaling in lung cancer to predict drug response. Histopathology, not just genetics, influences signaling pathways like MAPK and AKT, guiding combination therapy selection.

Area of Science:

  • Oncology
  • Molecular Biology
  • Precision Medicine

Background:

  • Functional heterogeneity in solid tumors is crucial for understanding therapeutic sensitivity in precision medicine.
  • Kras-driven non-small cell lung cancer (NSCLC) exhibits diverse histopathologies and complex oncogenic signaling.

Purpose of the Study:

  • To model spatial characteristics of oncogenic signaling and therapy response in precision-cut lung cancer slices.
  • To investigate the correlation between histopathology, signaling pathway activity, and drug sensitivity in NSCLC.

Main Methods:

  • Utilized precision-cut slice explants from Kras-driven NSCLC models with varying histopathologies.
  • Profiled in situ tumors to assess spatial signaling activities (AKT, SRC, MAPK, mTORC1).
  • Performed short-term drug treatments on slice explants to evaluate cytotoxic responses to combined pathway inhibition.

Main Results:

  • Oncogenic signaling stratified primarily by histopathology, with adenosquamous carcinoma showing enhanced AKT/SRC activity and adenocarcinoma showing enhanced MAPK activity.
  • Significant intertumour and intratumour variability in MAPK and mTORC1 activity was observed.
  • Cytotoxic responses to combined MAPK and phosphoinositide 3-kinase-mTOR inhibition correlated with spatially defined pathway activities.

Conclusions:

  • Histopathology, alongside spatially variable signaling activities, dictates drug sensitivity in NSCLC, rather than solely genetic drivers.
  • Spatial aspects of signaling heterogeneity should be considered in clinical diagnostics for guiding combination therapy selection in precision medicine.
Keywords:
non-small-cell lung canceroncogenic signallingprecision-cut slicesprostate cancerspatial heterogeneitytargeted therapy

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