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.

P1, N=42, Active, not recruiting, HUYABIO International, LLC. | Recruiting --> Active, not recruiting | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2026

P1, N=227, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Business reasons and not due to any safety concerns

Here, we show that SHP2 blockade, by using the SHP099 pharmacologic inhibitor or genetic approaches, significantly affected ATC cell viability, survival, proliferation, motility and stemness assessed by MTS, clonogenic, migration, sphere-forming assays, and Anx-V/PI staining...Consistently, in a syngeneic ATC mouse model, SHP2 inhibition caused an increase of proinflammatory and a decrease of immunosuppressive cytokines/chemokines concomitantly with an increased tumor infiltration of cytotoxic CD8+ T lymphocytes (6,0 ± 8,1 % vs 17,0 ± 8,4 %) and M1 macrophages (14,6 ± 7,6 % vs 29,3 ± 16,2 %) and a reduction in myeloid-derived suppressor cells (MDSCs) (8,5 ± 4,7 % vs 3,9 ± 1,8 %) compared to vehicle-treated group. These findings pose SHP2 as a critical mediator in ATC progression and underscore its potential as a therapeutic target due to its dual role in both directly impeding tumor growth and enhancing immune-mediated anti-tumor responses.

Furthermore, SFX-01 also attenuated JMML human patient-derived hematopoietic stem cell proliferation that was linked to STAT1 signaling and decreased cyclin D1 expression, resulting in cell-cycle arrest. We conclude that SFX-01 is an activating mutant Shp2 inhibitor and may offer beneficial effects in patients with JMML or Noonan syndrome.

P1, N=227, Active, not recruiting, Novartis Pharmaceuticals | Trial primary completion date: Nov 2025 --> Jul 2025 | Trial completion date: Nov 2025 --> Jul 2025

Finally, RIT1M90I drove resistance to the KRASG12C inhibitor, divarasib, and the combination with migoprotafib reverted this phenotype. Together, our data shows that RIT1M90I is a bona fide oncogenic driver of lung cancer and mediator of targeted therapy resistance as a co-occurring mutation and suggests that RIT1-altered cancer patients may benefit from combination treatments with a SHP2 inhibitor.

SHP099, an allosteric inhibitor for Src-homology domain-containing protein tyrosine phosphatase-2 (SHP2), and CPI-444, a selected inhibitor for adenosine A2AR receptor, were co-encapsulated in a T cell-targeting nanoparticle (SCNP/αCD8). The enhanced anti-tumor immunity in vivo is also ascribed to improved infiltration of effector CD8+ T cells in tumor tissues. These findings suggest that concurrent blockade of A2AR and SHP2 immune checkpoint signaling pathways with small molecule inhibitors offers a promising alternative strategy to enhance T cell functions for enhanced cancer immunotherapy.