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Updated: Jan 17, 2026

Generation of High-Throughput Three-Dimensional Tumor Spheroids for Drug Screening
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RAS Pathway Inhibitors Combined with Targeted Agents Are Active in Patient-Derived Spheroids with Oncogenic KRAS

Zahra Davoudi1, Thomas S Dexheimer1, Nathan P Coussens1

  • 1Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland.

Cancer Research Communications
|September 17, 2025
PubMed

Insights

Targeting Kirsten rat sarcoma viral oncogene homolog (KRAS) pathway inhibitors with small molecules showed significant anti-cancer activity. Combinations of direct KRAS inhibition and indirect pathway modulation effectively reduced tumor spheroid viability.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene is frequently altered in various cancers, with its protein historically considered undruggable.
  • Targeting oncogenic KRAS involves direct inhibition or indirect modulation of its signaling pathway mediators.

Purpose of the Study:

  • To identify effective small-molecule drug combinations targeting oncogenic KRAS signaling.
  • To evaluate the efficacy of direct KRAS inhibition combined with upstream or downstream pathway modulation in tumor spheroids.

Main Methods:

  • A high-throughput screen of multicell-type tumor spheroids was employed to identify synergistic drug combinations.
  • Inhibitors targeting KRAS G12C (sotorasib), SHP2 (batoprotafib), SOS1 (BI-3406), MEK (trametinib), ERK (temuterkib), PI3K/AKT/mTOR pathway components (sapanisertib, ipatasertib), and BCL-2 (venetoclax) were tested.
  • Combinations were assessed for their impact on tumor spheroid viability and pathway inhibition.

Main Results:

  • Single agents sotorasib and batoprotafib showed selectivity for KRAS G12C spheroids, while BI-3406 had variable activity.
  • Vertical inhibition of the RAS/MEK/ERK pathway (SHP2/SOS1 with MEK/ERK inhibitors) and dual inhibition of RAS/MEK/ERK and PI3K/AKT/mTOR pathways demonstrated significant efficacy.
  • Combinations involving sotorasib, batoprotafib, or BI-3406 with other targeted agents, including venetoclax, exhibited additive or synergistic anti-cancer activity, particularly in KRAS G12C-harboring spheroids.

Conclusions:

  • Targeting KRAS signaling through combinations of direct inhibitors and pathway modulators is a promising strategy for cancer therapy.
  • Specific combinations, including vertical and dual pathway inhibition, show significant potential for reducing tumor viability.
  • Further investigation into these KRAS-targeting combinations is warranted for clinical development.

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