TY - JOUR
T1 - Overcoming Resistance to the THZ Series of Covalent Transcriptional CDK Inhibitors
AU - Gao, Yang
AU - Zhang, Tinghu
AU - Terai, Hideki
AU - Ficarro, Scott B.
AU - Kwiatkowski, Nicholas
AU - Hao, Ming Feng
AU - Sharma, Bandana
AU - Christensen, Camilla L.
AU - Chipumuro, Edmond
AU - Wong, Kwok kin
AU - Marto, Jarrod A.
AU - Hammerman, Peter S.
AU - Gray, Nathanael S.
AU - George, Rani E.
N1 - Funding Information:
The authors thank members of the George and Gray labs for helpful discussions. Y.G. is supported by a Friends for Life Neuroblastoma Fellowship; T.Z., N.S.G., and R.E.G. are supported by the NIH (R01 CA197336); Y.G., N.S.G., and R.E.G. are supported by a Department of Defense Translational Team Science Award (W81XWH-15-PRCRP-TTSA). N.S.G. is a scientific founder, SAB member, and equity holder in Syros Pharmaceuticals, which is developing Cdk7 inhibitors and has licensed IP from the Dana-Farber Cancer Institute (DFCI). T.Z. is an inventor of THZ1, which is licensed from DFCI to Syros. N.K. is an inventor of THZ1, which is licensed from DFCI to Syros.
Funding Information:
The authors thank members of the George and Gray labs for helpful discussions. Y.G. is supported by a Friends for Life Neuroblastoma Fellowship; T.Z., N.S.G., and R.E.G. are supported by the NIH ( R01 CA197336 ); Y.G., N.S.G., and R.E.G. are supported by a Department of Defense Translational Team Science Award ( W81XWH-15-PRCRP-TTSA ). N.S.G. is a scientific founder, SAB member, and equity holder in Syros Pharmaceuticals, which is developing Cdk7 inhibitors and has licensed IP from the Dana-Farber Cancer Institute (DFCI). T.Z. is an inventor of THZ1, which is licensed from DFCI to Syros. N.K. is an inventor of THZ1, which is licensed from DFCI to Syros.
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2018/2/15
Y1 - 2018/2/15
N2 - Irreversible inhibition of transcriptional cyclin-dependent kinases (CDKs) provides a therapeutic strategy for cancers that rely on aberrant transcription; however, lack of understanding of resistance mechanisms to these agents will likely impede their clinical evolution. Here, we demonstrate upregulation of multidrug transporters ABCB1 and ABCG2 as a major mode of resistance to THZ1, a covalent inhibitor of CDKs 7, 12, and 13 in neuroblastoma and lung cancer. To counter this obstacle, we developed a CDK inhibitor, E9, that is not a substrate for ABC transporters, and by selecting for resistance, determined that it exerts its cytotoxic effects through covalent modification of cysteine 1039 of CDK12. These results highlight the importance of considering this common mode of resistance in the development of clinical analogs of THZ1, identify a covalent CDK12 inhibitor that is not susceptible to ABC transporter-mediated drug efflux, and demonstrate that target deconvolution can be accomplished through selection for resistance. Gao et al. report ABC transporter upregulation as a major mechanism of acquired resistance to the THZ series of covalent CDK7/12/13 inhibitors and describe the generation of E9, which escapes drug efflux and whose target selectivity was confirmed by the acquisition of a CDK12-binding site mutation in E9-resistant cells.
AB - Irreversible inhibition of transcriptional cyclin-dependent kinases (CDKs) provides a therapeutic strategy for cancers that rely on aberrant transcription; however, lack of understanding of resistance mechanisms to these agents will likely impede their clinical evolution. Here, we demonstrate upregulation of multidrug transporters ABCB1 and ABCG2 as a major mode of resistance to THZ1, a covalent inhibitor of CDKs 7, 12, and 13 in neuroblastoma and lung cancer. To counter this obstacle, we developed a CDK inhibitor, E9, that is not a substrate for ABC transporters, and by selecting for resistance, determined that it exerts its cytotoxic effects through covalent modification of cysteine 1039 of CDK12. These results highlight the importance of considering this common mode of resistance in the development of clinical analogs of THZ1, identify a covalent CDK12 inhibitor that is not susceptible to ABC transporter-mediated drug efflux, and demonstrate that target deconvolution can be accomplished through selection for resistance. Gao et al. report ABC transporter upregulation as a major mechanism of acquired resistance to the THZ series of covalent CDK7/12/13 inhibitors and describe the generation of E9, which escapes drug efflux and whose target selectivity was confirmed by the acquisition of a CDK12-binding site mutation in E9-resistant cells.
KW - covalent transcriptional CDK inhibitor
KW - drug resistance
KW - pediatric and adult solid tumors
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UR - http://www.scopus.com/inward/citedby.url?scp=85038876224&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2017.11.007
DO - 10.1016/j.chembiol.2017.11.007
M3 - Article
C2 - 29276047
AN - SCOPUS:85038876224
VL - 25
SP - 135-142.e5
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 2
ER -