Cotargeting of BCL2 and BCL-XL with VEN and A1155463 is synthetically lethal on a panel of PDX models derived from patients with MCL, ALL, and DLBCL. (A) Cotargeting of BCL2 and BCL-XL with VEN and A1155463 was tested on a panel of 9 PDX models including MCL (VFN-M1, VFN-M5R1, and VFN-M16), ALL (VFN-ALL1, VFN-ALL6, and VFN-ALL7), and DLBCL (VFN-D1, VFN-D9, and VFN-D20); x-axis shows days from initiation of therapy; y-axis shows calculated tumor volumes ± standard deviations of PDX tumors; therapy was administered on days 1 to 4 and 8 to 12 (for details, see “Methods”). (B) Cotargeting of BCL2 and BCL-XL with VEN and A1155463 was effective even in the PDX models with acquired VEN resistance (VFN-M1 VEN-R and VFN-ALL6 VEN-R); VEN-R PDX tumors were derived from animals, in which originally VEN-sensitive PDX tumors grew on continued VEN therapy; such VEN-R PDX tumors were re-engrafted into secondary recipients and subjected to retreatment; each cohort of mice comprised 6 animals.