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These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.<\/jats:p>","DOI":"10.3390\/ijms25020766","type":"journal-article","created":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T07:59:20Z","timestamp":1704700760000},"page":"766","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5500-3522","authenticated-orcid":false,"given":"Luca","family":"Pagliaro","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy"},{"name":"Hematology and BMT Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7622-5009","authenticated-orcid":false,"given":"Elisa","family":"Cerretani","sequence":"additional","affiliation":[{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy"},{"name":"Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9835-4063","authenticated-orcid":false,"given":"Federica","family":"Vento","sequence":"additional","affiliation":[{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy"},{"name":"Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Montanaro","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6080-7864","authenticated-orcid":false,"given":"Lucas","family":"Moron Dalla Tor","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7488-8642","authenticated-orcid":false,"given":"Elisa","family":"Simoncini","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8748-7012","authenticated-orcid":false,"given":"Mariateresa","family":"Giaimo","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy"},{"name":"Hematology and BMT Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Gherli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy"},{"name":"Hematology and BMT Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Zamponi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy"},{"name":"Hematology and BMT Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isotta","family":"Tartaglione","sequence":"additional","affiliation":[{"name":"Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Lorusso","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5813-9434","authenticated-orcid":false,"given":"Matteo","family":"Scita","sequence":"additional","affiliation":[{"name":"Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filomena","family":"Russo","sequence":"additional","affiliation":[{"name":"Hematology and BMT Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Sammarelli","sequence":"additional","affiliation":[{"name":"Hematology and BMT Unit, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giannalisa","family":"Todaro","sequence":"additional","affiliation":[{"name":"Hematology and BMT Unit, University Hospital of Parma, 43126 Parma, 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