P1/2, N=152, Not yet recruiting, Suzhou Genhouse Bio Co., Ltd.

In a murine model of MDA-MB-231-induced osteolytic lesions, oral administration of 10 mg/kg SHP099 reduces osteoclasts and prevents the trabecular bone loss. Our study identifies SHP2 as a druggable target for inhibiting breast cancer-induced osteoclast differentiation, positioning the specific inhibitors of SHP2 as potential drugs developed to treat tumour-induced osteolysis in the future.

Regimens co-targeting the MAPK pathway and ALK or ROS1 had limited efficacy in unselected patients with lorlatinib-resistant NSCLC, underscoring the need for more effective and biomarker-informed treatment strategies.

Notably, the combination of LPM5140276 and RMC4550 synergistically suppressed ERK and SHP2 phosphorylation, enhanced G0/G1 arrest and apoptosis, and improved the antitumor efficacy. Thus, LPM5140276 is a promising KRASG12D inhibitor, whose combination with SHP2 inhibition represents a viable strategy for overcoming resistance.

P1/2, N=46, Recruiting, Memorial Sloan Kettering Cancer Center | N=11 --> 46

P2, N=120, Not yet recruiting, Suzhou Genhouse Bio Co., Ltd.

P1, N=40, Completed, Jacobio Pharmaceuticals Co., Ltd. | Recruiting --> Completed | N=24 --> 40

Glecirasib combined with sitneprotafib showed promising efficacy and manageable safety in patients with advanced KRASG12C -mutated NSCLC, particularly among those who had not received previous treatment. These findings support the evaluation of this combination in a phase 3 trial comparing this chemotherapy-free regimen to current standard of care in this patient group.

G-LNP@S-D consists of GM1-functionalized liposomes co-encapsulating the SHP2 inhibitor SHP099 and the STING agonist DMXAA, enabling sequential lymph node- and CD169+ macrophage-specific drug delivery...Importantly, G-LNP@S-D exerts systemic immunomodulatory effects for directly eradicating lymphatic metastases. This study elucidates a sophisticated lymph node immune-modulation strategy and provides a promising therapeutic approach to treat lymphatic metastasis.

P1, N=10, Completed, Genentech, Inc. | Active, not recruiting --> Completed | N=172 --> 10 | Trial completion date: Dec 2026 --> Sep 2025 | Trial primary completion date: Dec 2026 --> Sep 2025

We herein demonstrated that the allosteric SHP2 inhibitors, SHP099 and TNO155, suppressed both the TNF-α- and growth factor-induced non-canonical phosphorylation of EphA2 at Ser-897 via the ERK-RSK pathway. In contrast, these inhibitors did not affect the signaling pathways leading to EphA2 induced by TPA in HeLa cells or by TNF-α in A549 cells, indicating the involvement of a complex signaling network in these processes. Collectively, the present results highlight the potential of allosteric SHP2 inhibitors as agents targeting the non-canonical activation of EphA2 in LUAD cells.

We found that both cobimetinib and daytime RMC-4550 similarly reduced tumor volume. Diurnal patterns of monocyte trafficking were disrupted in tumor-bearing mice, and SHP2 inhibition reduced tumor volume only when administered during the day, when myeloid infiltration was low. These findings suggest that SHP2 inhibitor-driven tumor shrinkage requires targeting monocyte-derived macrophages and is influenced by the timing of drug administration.