RAS Mutation-Specific Responses to Paralog- and State-Selective RAS Inhibitors | JoVE Visualize

Area of Science:

Oncology
Molecular Biology
Pharmacology

Background:

A high therapeutic index is crucial for effective cancer therapies, requiring potent inhibition of oncogenic signaling in tumor cells with minimal impact on normal cells.
Recent advancements include diverse RAS-targeting inhibitors, such as mutant-specific (KRAS G12C, KRAS G12D) and paralog- or state-selective inhibitors.
Non-mutant-specific RAS inhibition strategies include targeting guanine nucleotide exchange factors (SHP2, SOS1), KRAS-OFF inhibitors, and active-state RAS(ON) inhibitors.

Purpose of the Study:

To define the signaling inhibition index (SII) for state- and paralog-selective RAS inhibitors.
To evaluate the differential suppression of oncogenic signaling between RAS-mutant and normal cells across various models.
To inform the design and clinical application of RAS-targeted therapies for improved tumor selectivity and outcomes.

Main Methods:

Evaluation of the signaling inhibition index (SII) for state- and paralog-selective RAS inhibitors.
Testing across diverse RAS-mutant and RAS-wild-type cellular and xenograft models.
Comparative analysis of different RAS inhibition strategies: guanine nucleotide exchange-OFF, KRAS-OFF, and active-state RAS(ON) inhibitors.

Main Results:

Guanine nucleotide exchange-OFF inhibitors showed neutral or negative SII, with reduced MAPK suppression in KRAS G12X cells versus wild-type.
KRAS G13D models, particularly with NF1 loss, demonstrated low sensitivity; SHP2 plus MEK inhibition yielded low selectivity.
RAS Q61X models were resistant due to MEK inhibitor-induced NRAS reactivation and altered SHP2 conformations; KRAS-OFF inhibitors showed higher selectivity.
Active-state RAS(ON) inhibitors exhibited broader activity but narrow selectivity.
Sensitivity to mutant-specific inhibitors largely overlapped with state-selective agents, indicating poor response to current RAS inhibitors for most RAS-mutant tumors.

Conclusions:

Current state- and paralog-selective RAS inhibitors often lack sufficient tumor selectivity, as indicated by their signaling inhibition index (SII).
Guanine nucleotide exchange-OFF and active-state RAS(ON) inhibitors demonstrate limitations in efficacy and selectivity across different RAS mutations and contexts.
Most RAS-mutant tumors are predicted to have a poor response to currently available RAS inhibitors, necessitating further development of more selective therapeutic strategies.