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The NOTCH gene

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The NOTCH gene

What is NOTCH?

The NOTCH gene codes for a family of receptor proteins that are important for communication with other cells. The NOTCH proteins (NOTCH1, 2, 3 and 4) are involved in cell development, growth and division [1].

Why is it important?

The NOTCH proteins are altered in various cancers, including adenoid cystic carcinoma (ACC) [2]. These changes in the protein cause it to become overactive, driving cancer growth [3].

What is the evidence?

The NOTCH gene is altered and overactive in in about 20% of ACC cases [3]. A large study of 1045 patients showed that these alterations were mostly in NOTCH1 [4].

Are treatments available?

This better understanding of the NOTCH gene has directly led to the development of drugs that block this pathway. One such drug, AL101 (osugacestat), has been investigated in clinical trials for ACC patients with NOTCH mutations [5]. One completed trial (NCT03691207), focused on ACC patients whose cancer has either returned or spread. The results showed that across both doses tested, 12% of patients experienced some degree of tumour shrinkage [6]. A second trial (NCT04973683) is active and is looking at the side effects and potential benefits of giving AL101 to patients before they undergo surgery for ACC [7].

Useful resources

Read more about how to get your tumour profiled and add to a research biobank here:

References

  1. Zhou B, Lin W, Long Y, Yang Y, Zhang H, Wu K, et al. Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduction and Targeted Therapy. 2022; 7(1):95.
  2. Karpinets TV, Mitani Y, Liu B, Zhang J, Pytynia KB, Sellen LD, et al. Whole-Genome Sequencing of Common Salivary Gland Carcinomas: Subtype-Restricted and Shared Genetic Alterations. Clin Cancer Res. 2021; 27(14):3960-9.
  3. Ferrarotto R, Mitani Y, Diao L, Guijarro I, Wang J, Zweidler-McKay P, et al. Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors. J Clin Oncol. 2017; 35(3):352-60.
  4. Ho AS, Ochoa A, Jayakumaran G, Zehir A, Valero Mayor C, Tepe J, et al. Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma. J Clin Invest. 2019; 129(10):4276-89.
  5. Ferrarotto R, Mishra V, Herz E, Yaacov A, Solomon O, Rauch R, et al. AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling. Cell Death & Disease. 2022; 13(8):678.
  6. Ferrarotto R, Metcalf R, Rodriguez C, Muzaffar J, Even C, Perez C, et al. Results of ACCURACY: A phase 2 trial of AL101, a selective gamma secretase inhibitor, in subjects with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) harboring Notch activating mutations (Notch mut ). Journal of Clinical Oncology. 2022; 40:6046.
  7. ClinicalTrials.gov (2025). AL101 Before Surgery for the Treatment of Notch Activated Adenoid Cystic Cancer (Identifier: NCT[NCT04973683]). Available online: https://clinicaltrials.gov/study/NCT04973683?intr=AL101&rank=3 (Accessed: 07/10/2025).

Last Updated December 2025