Table 1.
Summary of resistance mechanisms to venetoclax therapy.
| Pathways of Resistance | Reported Examples of Mechanisms of Resistance |
Type of Malignancy |
Type of Study | Reference |
|---|---|---|---|---|
| BCL2 mutations of venetoclax-binding site | Gly101Val mutation * | CLL | Patients derived samples | [51] |
| Phe104Leu/Cys mutations | DLBCL, FL, MCL, and leukemia cell lines |
In vitro (preclinical) | [52] | |
| Alternative anti-apoptotic proteins pathways | Overexpression of BCL-XL, MCL-1, and BFL-1. | CLL | Patients derived samples | [53] |
| Amp1q leading to MCL-1 overexpression | CLL | In vitro (preclinical) followed by patients derived samples | [54] | |
| Kinase-mediated survival signals leading to BCL-XL, MCL-1, and A1 | CLL | Patients derived samples | [47] | |
| MCL-1 overexpression | AML | In vitro (preclinical) | [42] | |
| MCL-1 overexpression | AML | In vitro (preclinical) | [43] | |
| PI3K/mTOR pathway and BCL-2 → MCL-1 overexpression | AML | In vitro (preclinical) | [45] | |
| Cyclin-dependent kinase 9 inhibition (CDK-9) → MCL-1 overexpression | DLBCL | In vitro (preclinical) | [46] |
Abbreviations: CLL: chronic lymphoid leukemia, DLBCL: diffuse large B-cell lymphoma, FL: follicular lymphoma, MCL: mantle cell lymphoma, and AML: acute myeloid leukemia. * Resistance 19–42 months after being initially responsive to venetoclax.