Targeting phenotypic plasticity prevents metastasis and the development of chemotherapy-resistant disease

Cancer cells invoke phenotypic plasticity programs to drive disease progression and evade chemotherapeutic insults, yet until now there have been no validated clinical therapies targeting this process. Here, we identify a phenotypic plasticity signature associated with poor survival in basal/triple-negative breast cancer, in which androgen signalling is prominent. We establish that anti-androgen therapies block cancer stem cell function and prevent chemotherapy-induced emergence of new cancer stem cells. In particular, the anti-androgen agent seviteronel synergizes with chemotherapy to improve chemotherapeutic inhibition of primary and metastatic tumour growth and prevent the emergence of chemotherapy-resistant disease. We validate cytoplasmic AR expression as a clinical phenotypic plasticity biomarker that predicts poor survival and poor response to chemotherapy, and positive response to seviteronel plus chemotherapy. This new targeted combination therapy validates modulating phenotypic plasticity as an effective strategy to prevent and treat chemotherapy-resistant cancers with transformative clinical potential. STATEMENT OF SIGNIFICANCEThere are currently no curative therapies for patients with chemotherapy-resistant cancer. We demonstrate that modulating phenotypic plasticity prevents the emergence of chemotherapy-resistant disease in triple-negative breast cancer. This represents the first known validated clinical therapy leveraging phenotypic plasticity. Moreover, we identify a highly effective anti-androgen drug and a biomarker to select and treat patients best-suited to this new therapy. A clinical trial is underway (NCT04947189). SUMMARY SENTENCEBlocking phenotypic plasticity is an effective targeted therapeutic strategy to treat cance