Emerging breakthroughs in targeted therapies warrant attention, including antisense oligonucleotides targeting MYB-NFIB fusion genes, clinical trial data of NOTCH inhibitors (e.g., AL101), and PARP inhibitor-based combinatorial regimens leveraging DNA damage repair mechanisms. By integrating fundamental research and clinical translational evidence, this review provides a theoretical framework for optimizing LGACC diagnosis and treatment paradigms.

Notably, lycorine enhanced the antitumor activity of osimertinib against its resistant cells both in vitro and in vivo. Overall, our data reveal that lycorine inhibits the proliferation and metastasis of osimertinib-resistant NSCLC cells via Notch3/Hes1 pathway.

NOTCH inhibitors demonstrate activity in NOTCH-activated ACC, surpassing the efficacy of observation or prior systemic therapies. However, limited PFS and progression of nontarget lesions suggest the potential need for combination therapy to address ACC heterogeneity.

P1, N=14, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1, N=14, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P2, N=18, Terminated, Ayala Pharmaceuticals, Inc, | N=67 --> 18 | Active, not recruiting --> Terminated; Sponsor's decision

P2, N=87, Completed, Ayala Pharmaceuticals, Inc, | Active, not recruiting --> Completed

Clinically, high expression of NOTCH3, miR-223 or low expression of ZEB1 were related to good prognosis of breast cancer patients. The current study reports a novel NOTCH3/miR-223/ZEB1 axis, which can inhibit the proliferation and invasion of breast cancer cells, and may serve as a potential biomarker for the prognosis of breast cancer.

*Inverse variance method, no transformation, 0.5 continuity correction. ORR: CR + PR; DCR: CR + PR + SD Conclusions AL101 showed acceptable safety and tolerability in ACC pts with Notchmut and a response rate comparable to pooled estimates for available therapies in pts regardless of Notch status.

Ni included AL101, a gamma-secretase inhibitor, or OMP-52M51, an antibody targeting N1...The efficacy of Ni compares favorably with efficacy of systemic therapies administered prior to Ni. The limited PFS and high rate of tumor progression on non-target lesions suggests Ni combination therapy may be necessary to address ACC heterogeneity.

TFLS could suppress the growth of breast cancer and eliminate breast cancer stem cells by inhibiting the Notch3 signaling pathway.

The therapeutic benefit of TKF against liver fibrosis results from inhibition of YAP and Notch3-Hes1 pathways, indicating that TKF may be a novel therapeutic candidate for liver fibrosis.