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Here, we identify the pro\u2010survival BCL\u20102 protein family member MCL\u20101 as a resistance factor for the BCL\u20102 inhibitor venetoclax in non\u2010Hodgkin lymphoma (NHL) cell lines and primary NHL samples. Mechanistically, we show that the antibody\u2010drug conjugate polatuzumab vedotin promotes MCL\u20101 degradation via the ubiquitin\/proteasome system. This targeted MCL\u20101 antagonism, when combined with venetoclax and the anti\u2010CD20 antibodies obinutuzumab or rituximab, results in tumor regressions in preclinical NHL models, which are sustained even off\u2010treatment. In a Phase Ib clinical trial (NCT02611323) of heavily pre\u2010treated patients with relapsed or refractory NHL, 25\/33 (76%) patients with follicular lymphoma and 5\/17 (29%) patients with diffuse large B\u2010cell lymphoma achieved complete or partial responses with an acceptable safety profile when treated with the recommended Phase II dose of polatuzumab vedotin in combination with venetoclax and an anti\u2010CD20 antibody.<\/jats:p>","DOI":"10.1002\/ajh.26809","type":"journal-article","created":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T07:30:55Z","timestamp":1672731055000},"page":"449-463","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Targeting MCL\u20101 and BCL\u20102 with polatuzumab vedotin and venetoclax overcomes treatment resistance in R\/R non\u2010Hodgkin lymphoma: Results from preclinical models and a Phase Ib study"],"prefix":"10.1002","volume":"98","author":[{"given":"Elisabeth A.","family":"Lasater","sequence":"first","affiliation":[{"name":"Department of Translational Oncology Genentech, Inc.  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