Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling.

Area of Science:

• Oncology
• Molecular Biology
• Immunotherapy

Background:

• Receptor tyrosine kinase (RTK) signaling drives many cancers and is often activated in response to targeted therapies.
• SHP2 inhibitors offer a novel approach to target RTK signaling pathways.
• Understanding the synergistic potential of SHP2 inhibitors in combination therapies is crucial for clinical development.

Purpose of the Study:

• To evaluate the efficacy and synergistic mechanisms of combinations involving the novel SHP2 inhibitor TNO155.
• To explore TNO155's potential in combination with EGFR inhibitors, BRAF inhibitors, KRAS^G12C inhibitors, CDK4/6 inhibitors, and anti-PD-1 antibodies.
• To provide a rationale for the clinical development of these combination strategies.

Main Methods:

• Testing combinations of TNO155 with various targeted agents in relevant cancer models in vitro and in vivo.
• Examining the effects of these combinations on downstream signaling pathways.
• Utilizing patient-derived xenografts for efficacy assessment.

Main Results:

• TNO155 combined with EGFR inhibitors showed benefit in EGFR-mutant lung cancer, sustaining ERK inhibition.
• TNO155 synergized with BRAF and MEK inhibitors in BRAF^V600E colorectal cancer by blocking ERK feedback.
• TNO155 enhanced the efficacy of KRAS^G12C inhibitors by blocking feedback activation of RAS.
• Combinations of TNO155 with CDK4/6 inhibitors demonstrated benefit in lung and colorectal cancer models.
• TNO155 inhibited CSF1R-mediated RAS activation and showed combination activity with anti-PD-1 antibodies.

Conclusions:

• TNO155 effectively blocks tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers.
• The findings support the clinical evaluation of TNO155 in combination with targeted therapies and immunotherapy.
• TNO155 demonstrates broad applicability in various cancer models, including those with KRAS mutations.