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The Ras Gene02:38

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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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RAS Pathway Inhibitors Combined with Targeted Agents Are Active in Patient-Derived Spheroids with Oncogenic KRAS

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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.

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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.