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Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism

Piro Lito1, Martha Solomon2, Lian-Sheng Li3

  • 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rosenn@mskcc.org litop@mskcc.org.

Science (New York, N.Y.)
|February 4, 2016
PubMed

Insights

New therapies can inhibit KRAS(G12C) signaling by trapping the protein in its inactive state, requiring intact guanosine triphosphatase (GTPase) activity. This mechanism offers a novel approach for treating KRAS(G12C)-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • KRAS oncoproteins are constitutively active due to disabled guanosine triphosphatase (GTPase) activity.
  • Drugs targeting inactive KRAS conformations are generally considered ineffective.
  • KRAS mutations, particularly G12C, are common drivers in various cancers.

Purpose of the Study:

  • To elucidate a novel mechanism for inhibiting KRAS(G12C) signaling and cancer cell growth.
  • To investigate the role of GTPase activity and nucleotide exchange in drug efficacy.
  • To provide a rationale for developing targeted therapies against KRAS(G12C)-driven cancers.

Main Methods:

  • Investigated drug inhibition of KRAS(G12C) signaling in cancer cells.
  • Assessed the requirement of GTPase activity for drug efficacy.
  • Examined the impact of nucleotide exchange factors on drug potency.
  • Evaluated the effect of modulating nucleotide exchange activity on KRAS(G12C) inhibition.

Main Results:

  • Drug-bound KRAS(G12C) is trapped in an inactive state, requiring intact GTPase activity for inhibition.
  • Mutants lacking GTPase activity or those promoting nucleotide exchange reduced drug potency.
  • Suppression of nucleotide exchange enhanced KRAS(G12C) inhibition, while potentiation reduced it.
  • KRAS(G12C) undergoes nucleotide cycling in cancer cells.

Conclusions:

  • KRAS(G12C) inhibitors function by trapping the oncoprotein in its inactive GDP-bound state.
  • Intact GTPase activity and suppressed nucleotide exchange are crucial for effective KRAS(G12C) inhibition.
  • These findings pave the way for developing novel therapies targeting KRAS(G12C)-driven malignancies.

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