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

By P. Lito, Martha Solomon, Lian-Sheng Li, R. Hansen, N. Rosen. Science, 2016

629 citations recorded by the source corpus.

Cancer therapy by entrapment Mutations in the KRAS oncogene occur at high frequency in several of the most lethal human cancers, including lung and pancreatic cancer. Substantial effort has thus been directed toward developing KRAS inhibitors. KRAS encodes an enzyme that binds the nucleotide GTP and hydrolyzes it to GDP. It had been thought that oncogenic mutations disable this hydrolytic activity, locking KRAS in the GTP-bound, active state. Surprisingly, Lito et al. found that a certain KRAS mutant (G12C) retains hydrolytic activity and continues to cycle between its active and inactive states. They describe a compound that inhibits KRAS(G12C) signaling and tumor cell growth by binding to the GDPbound form of KRAS, trapping it in its inactive state. Science, this issue p. 604 A surprising mechanistic insight may lead to drugs targeting an oncogenic form of KRAS expressed in lung cancer. It is thought that KRAS oncoproteins are constitutively active because their guanosine triphosphatase (GTPase) activity is disabled. Consequently, drugs targeting the inactive or guanosine 5′-diphosphate–bound conformation are not expected to be effective. We describe a mechanism that enables such drugs to inhibit KRASG12C signaling and cancer cell growth. Inhibition requires intact GTPase activity and occurs because drug-bound KRASG12C is insusceptible to nucleotide exchange factors and thus trapped in its inactive state. Indeed, mutants completely lacking GTPase activity and those promoting exchange reduced the potency of the drug. Suppressing nucleotide exchange activity downstream of various tyrosine kinases enhanced KRASG12C inhibition, whereas its potentiation had the opposite effect. These findings reveal that KRASG12C undergoes nucleotide cycling in cancer cells and provide a basis for developing effective therapies to treat KRASG12C-driven cancers.

Subfields: Cell Biology, Materials Chemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e165d3c03cf60d1cdc247a235e53363d62727803

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. C. V. Dang
2. Christopher Sander
3. N. Bardeesy

In Materials Chemistry

1. Jeffrey Roach
2. Christopher Sander
3. Matthew Meyerson

In Molecular Biology

1. Peter W. Laird
2. Hui Shen
3. S. Baylin
4. Eric S. Lander
5. Timothy Triche
6. Gad Getz
7. Matthew Meyerson
8. P. Park

Citations in the corpus

• The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients (2019, background): “Indeed, introducing a comutation that impairs the GTPase activity of KRASG12C (24) attenuated the inhibitory activity of MRTX1257, a close analogue of MRTX849 (Supplementary Fig.”
• Drugging the ‘undruggable’ cancer targets (2017, positive): “Although the initial compound required high micromolar concentrations for biological activity in cell culture assays, second-and third-generation compounds were much more active in their ability to inhibit KRAS signalling 12,13 .”
• Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma (2017, positive): “As therapeutic discovery efforts progress toward development of allele-specific smallmolecule inhibitors of the KRAS protein (Lito et al., 2016; Ostrem et al., 2013), the finding of multiple oncogenic KRASmutations in the same sample may have important clinical ramifications, including the increased”
• Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. (2018, background): “In contrast, the S-IIP class of covalent KRAS inhibitors (Lito et al., 2016; Ostrem et al., 2013; Patricelli et al., 2016), despite their initial lack of potency, can produce very specific and demonstrably targeted effects on the mutant allele in cells.”