Possible therapeutic compounds for LUAD patients included SHP-099, Dimethylfasudil, EMD-534085, and PF-2771. The expression of CTCFL enhanced the malignant cellular behavior in LUAD. ZNFs-related gene signature provides predictive insights into LUAD patient survival, immune cell infiltration, and immune checkpoint blockade therapy, serving as a valuable tool to guide clinical decision-making.

P1/2, N=200, Active, not recruiting, Erasca, Inc. | Trial completion date: Nov 2025 --> Jan 2027 | Trial primary completion date: May 2025 --> Nov 2026

A4 effectively inhibited proliferation in SHP099-insensitive tumor cell lines and reversed programmed cell death ligand 1 (PD-L1)-mediated immunosuppression. Furthermore, A4 displayed significant in vivo antitumor efficacy in an MDA-MB-231 mouse model and strongly promoted in vivo antitumor immunity in a 4T1 mouse model. Our results identified A4 as a promising dual SHP2 and NAMPT inhibitor, providing a novel therapeutic strategy for overcoming resistance to allosteric SHP2 inhibition.

Sufficient exposure to RMC-4630 and LY3214996 was not reached due to the toxicity profile of the combination. Tumor response was not demonstrated at the explored dose levels. Therefore, the dose escalation was discontinued, and the RP2D was not determined.

P1/2, N=12, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=46 --> 12

P1, N=90, Active, not recruiting, Erasca, Inc. | N=200 --> 90 | Trial completion date: Feb 2026 --> Jun 2026 | Trial primary completion date: Nov 2025 --> Feb 2026

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.