Table 1 Synthetic lethal interaction of IDH compromise and the development of combinatorial treatment regimens.

TMZ, temozolomide; BPTES, bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide; Mcl-1, induced myeloid leukemia cell differentiation protein; Bcl-xL, B cell lymphoma–extra large; RT, radiotherapy; MYC, myelocytomatosis; BET, bromo- and extra-terminal domain; CCNU, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

IDH mutant
disease/cell lines
Synthetic lethal interactionTherapeutic regimenReference
GliomaReduction in NAD+ levels and vulnerability to NAD+ depletionNAMPT inhibitor (GMX-1778)(89)
GliomaPARP-mediated DNA repair after chemotherapy-induced
DNA damage
Temozolomide and NAMPT inhibitor(104)
MPNsGain-of-function mutations in JAK/STATCo-inhibition of JAK2 and mutant IDH1 and IDH2(106)
AML(R)-2HG inhibits cytochrome c oxidase, lowering the threshold
for apoptosis induction in response to Bcl-2 inhibition
Bcl-2 inhibitor ABT-199(107)
ICCsIncreased sensitivity to inhibition of nonreceptor tyrosine
kinase SRC
Dasatinib(108)
Mammary epithelialIDH1-R132H cells have compromised ability to obtain energy
from major sources of cellular carbon and are dependent
on glutamine
Metformin alone or with glutaminase inhibitor
BPTES or IDH1-R132H inhibitor AG5918
(125)
Glioblastoma and glioma(R)-2HG results in low levels of Mcl-1 and increased sensitivity
to inhibition of Bcl-xL
Bcl-xL inhibitor ABT-263(126)
GlioblastomaOverexpression of IDH1-R132H enhanced the cytotoxic effect
of radiation through altered ROS metabolism
Radiation therapy(127)
Primary low-grade gliomasMYC pathway is activated in patient-derived tumors and
makes cells sensitive to BET inhibitors
Brd inhibitors JQ1 and GS-626510(128)
Glioblastoma(R)-2HG inhibits ALKBH2 and ALKBH3 DNA repair enzymes
sensitizing cells to alkylating agents
Alkylating agents busulfan, procarbazine, CCNU,
or vincristine
(129)
GlioblastomaGlutaminase converts glutamine to glutamate, then converted
to αKG and then to 2HG
Glutaminase inhibitor BPTES(130)
Glioma2HG inhibits BCAT1 and BCAT2, which are used by the cells to
convert BCAA into glutamate. This makes the cells even
more reliant on glutaminases for glutamate biosynthesis
Glutaminase inhibitor CB-839 and RT or TMZ(58)
AMLIDH1-R132H cells have increased ACACA gene expression
compared to wild type
ACACA inhibitor TOFA(131)