Page 57 - Read Online

Page 132 Saliba et al. Cancer Drug Resist 2021;4:125-42 I http://dx.doi.org/10.20517/cdr.2020.95

lymphocytic leukemia (CLL) in early human studies [122] . However, navitoclax also displayed dose-limiting
thrombocytopenia [123,124] that was traced to involvement of BCLX in platelet survival [125] . To avoid this
L
toxicity, venetoclax was engineered to specifically inhibit BCL2 only [126] . Venetoclax sensitivity was shown
to be BCL2-dependent, with decreased lethality in platelets and nanomolar potency in the BCL2-dependent
disease CLL [122,126-128] .

As a BH3 mimetic, venetoclax is thought to act primarily by binding to BCL2, causing release of
sequestered BAX and BAK, thereby leading to MOMP and apoptosis [117,119,129] . More specifically, venetoclax
has been shown to form a hydrogen bond at Asp103 in BCL2 and interact with the intercalating indole on
a partner BCL2 [126] . Alternatively, it has also been suggested that venetoclax might also lead to cell death
by destabilizing the proton gradient across the mitochondrial inner membrane, leading to acidification
of the cytosol and metabolic crisis [130] . Whatever the proximate action of venetoclax, the final outcome is
MOMP and release of cytochrome c to the cytoplasm, thereby resulting in apoptosome formation as well as
decreased ATP production due to diminished mitochondrial cytochrome c [131,132] .

Biomarkers that predict response to venetoclax are not fully understood. Venetoclax was initially approved
for the treatment of relapsed CLL with chromosome 17p loss [122] . High BCL2 protein in this disease [133] ,
which results from deletion of genes encoding two microRNAs that target BCL2 mRNA [134,135] , was taken as
a sign that CLL might be dependent on BCL2 for survival and, therefore, sensitive to BCL2 inhibition.

The correlation between high expression of BCL2 protein and sensitivity also appears to hold for other
neoplasms, but this relationship can be lost when high levels of venetoclax-insensitive BCL2 paralogs
such as MCL1 are expressed [126,136] . In secondary AML refractory to HMAs, an increase in BCL2 and/or
BIM protein detected by immunohistochemistry in myeloblasts in pretreated bone marrow aspirates was
strongly associated with venetoclax monotherapy response and overall survival [137] . In a phase II, single-
arm clinical study of venetoclax monotherapy at a dose of 800 mg daily in patients with relapsed/refractory
AML or patients with previously untreated AML who were unfit for conventional chemotherapy, an
objective response rate of 19% (6 of 32 patients) was observed, with 6% (2 of 32 patients) achieving CR [138] .
As described below, high expression of BCL2 relative to other anti-apoptotic BCL2 family members was
associated with better outcomes.

Mechanisms of resistance to venetoclax monotherapy
Mechanisms of resistance in early trials of venetoclax in CLL were well studied [136,139-142] . De novo resistance was
attributable to a lack of BCL2 dependence, either because BCL2 was not activated or the CLL depended upon
other paralogs such as MCL1 or BCLX L [143-145] . Selection of cells that are dependent on an alternative BCL2
family member, such as BCLX or MCL1, was also a major mechanism of acquired resistance [Figure 2] [146-148] .
L
This mechanism is not limited to CLL. Overexpression of MCL1 and/or BCLX may play a major role in the
L
pathogenesis of various types of leukemia and mediate venetoclax resistance if BCL2 overexpression is not
the primary antiapoptotic driver. In venetoclax-resistant AML cell lines, concurrent inhibition of MCL1
can mitigate venetoclax resistance [149-151] . Combining venetoclax with daunorubicin or cytarabine has been
[150]
shown to reverse some of the BIM sequestration mediated by MCL1, also sensitizing AML to venetoclax .
In T-cell acute lymphoblastic leukemia cells with both MCL1 and BCL2 overexpression, combination
therapy with inhibitors of both MCL1 (S63845) and BCL2 (venetoclax) is highly efficacious [152] .

A number of additional mechanisms of venetoclax resistance have been described. One involves the
acquisition of mutations within BCL2 itself, such as the Gly101Val mutation, which prevents or reduces
venetoclax binding [136,139-141,153] . Mutations in the transmembrane domain of BAX have also been shown to
prevent mitochondrial anchoring of BAX, thereby preventing BAX from facilitating MOMP and inducing