PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)

P1, N=64, Terminated, Mirati Therapeutics Inc. | Phase classification: P1/2 --> P1 | N=228 --> 64 | Trial completion date: Jul 2026 --> Feb 2026 | Active, not recruiting --> Terminated | Trial primary completion date: Jun 2026 --> Feb 2026; business objectives have changed

P2, N=29, Active, not recruiting, University of Utah | Trial primary completion date: Jan 2026 --> Apr 2025

Undescribed features in this group included myopathy and megacolon in a patient with Noonan syndrome-like, hypogonadotropic hypogonadism, and azoospermia in a patient with Noonan syndrome-like with loose anagen hair, and schizophrenia in a patient with Costello syndrome. One patient with Noonan syndrome had a novel variant of the A2ML1 gene (c.1829G>A), but the variant was strictly of uncertain significance, while c.2033G>A in the LZTR1 gene and c.1A>G in the NF1 gene are variants for the first time associated with features of Noonan syndrome.

Mechanistically, EHDPP binds to EGFR and inhibits its ubiquitination-mediated degradation, thereby stabilizing EGFR protein and partly activating the downstream PI3K-AKT signaling pathway, which ultimately promotes lung cancer cell proliferation and migration. This study is the first to elucidate the molecular mechanism underlying the pro-carcinogenic effects of EHDPP at the interaction level, providing potential molecular marker clues and mechanistic basis for EHDPP-related environmental risk assessment.

P1, N=40, Recruiting, M.D. Anderson Cancer Center | N=20 --> 40

Functional validation of novel, recurrent PTPN11 variants confirmed gain-of-function, while cellular modeling in induced pluripotent stem cells demonstrated proliferative/survival advantages for mutant cells in mosaic culture. Overall, our data suggest that somatic Ras-MAPK variants and acquired risk factors may converge on clonal competition in the hippocampus to modulate epilepsy risk.

Notably, our MD simulations reveal transient but relevant interactions involving N-terminal residues that are not detectable in crystallographic structures. These findings lay the groundwork for designing peptide inhibitors that specifically target the C-SH2 domain of SHP2.

PTPN11 -related NS predisposes to multifocal pure and mixed LGGs confirmed by radiological, histological, and molecular characteristics. Targeting FGFR1-related pathways may provide new treatment approaches for patients with NS and LGGs.

Cells were treated with VEN, the MCL-1 inhibitor S63845 and the mitogen-activated protein kinase (MEK) inhibitor trametinib (TRA), alone or in combination. The presented results highlight the role of MAPK-driven MCL-1 and BCL(x)L expression, which mediates VEN resistance. While dual inhibition of B-cell lymphoma 2 and MCL-1 is already effective, additional MEK inhibition may further improve outcomes in PTPN11-mutated AML.

P2, N=29, Active, not recruiting, University of Utah | Recruiting --> Active, not recruiting

Our study demonstrates that patients with eAML subtype have a worse prognosis, unique molecular features and higher tumor burden. Allo-HSCT might be an effective way to improve prognosis. This study provides evidence critical for risk stratification and treatment optimization in eAML.

We then describe new developments concerning catalytic and non-catalytic functions of SHP2, as well as recent progress in the understanding of SHP2 regulation, including it being subjected to SUMOylation, activated independently of cell surface receptors, and regulated by substrate phosphorylation. These new insights not only demonstrate the complexity of SHP2 regulation but also guide future studies, contributing important insights that could aid in targeting SHP2 in different disease contexts in the future.