Overall, our results demonstrate at a preclinical level that the combination of danusertib or volasertib and AZD1775 (or other, equivalent inhibitors that could rapidly be repurposed) is a promising option capable to counteract BCR::ABL1-independent TKI resistance and to kill CD34+ LSC progenitors of BC patients, while leaving normal HSCs unaffected. The gene discussed is BCR; the disease is breast cancer.