Project B

Targeting Plasticity and Cell Cycle Checkpoints to Induce Synthetic Lethality in Liver Cancers

Epithelial-mesenchymal plasticity (EMP) promotes cancer metastasis and therapy resistance, endowing cancer cells with the ability to reversibly switch between rapidly cycling epithelial stem-like and slow-cycling mesenchymal, fibroblast-like, phenotypes (Fig. 2A)(1-3).  EMP and the cell cycle are tightly interlinked through, e.g., the cell cycle inhibitors p16INK4 (CDKN2A), p21CIP1 (CDKN1A), and p27KIP1 (CDKN1B) that control cancer cell cycle progression, migration, and invasion in an EMP state-dependent manner (3, 4).  Likewise, the central EMP transcription factor ZEB1 controls cell cycle decisions through physical interactions with proteins that regulate the G1/S DNA repair checkpoint, including ataxia telangiectasia mutated (ATM).  Strikingly, RNAi-mediated knockdown of ZEB1 activated replication stress and DNA repair signaling through ataxia telangiectasia and Rad3-related protein and the checkpoint kinase-1 (ATR, and CHEK1), and sensitized cancer cells to ATR inhibition (5, 6); this represents a case of induced synthetic lethality in otherwise therapy resistant, mesenchymal cancer cells (7, 8).  We discovered that inhibiting EMP-driving kinases like the adapter associated kinase 1 (AAK1) activated the cell cycle in mesenchymal hepatocellular carcinoma (HCC) cells (Fig. 2B), which was accompanied by increased DNA repair and replication stress signaling (Fig. 2C) and an up to 20-fold increased sensitivity to CHEK1 inhibition (Fig. 2D)(9, 10).  EMP transcription factors like ZEB1 are difficult to target with pharmacological inhibitors, however, kinases are highly druggable (11, 12).  We hypothesize that inhibiting EMP-driving kinases can serve as a surrogate for targeting EMP transcription factors to reverse EMP and enhance replication stress, thereby inducing synthetic lethality with inhibitors of checkpoint kinases and chemotherapy in otherwise therapy resistant cancers.  Going forward, we will systematically identify kinases that link EMP with DNA repair signaling and replication stress, and we will develop novel combination therapies that induce synthetic lethality in therapy resistant, mesenchymal tumors.  Long-term, we seek to translate these combination therapies into the clinic to combat advances, metastatic tumors.

References

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6.  Song N, Jing W, Li C, Bai M, Cheng Y, Li H, Hou K, Li Y, Wang K, Li Z, Liu Y, Qu X, Che X. ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial-mesenchymal transition and enhancing DNA damage. Cell Cycle. 2018;17(5):595-604. doi: 10.1080/15384101.2017.1404206. PubMed PMID: 29157079; PMCID: PMC5969561.

7.  Cybulla E, Vindigni A. Leveraging the replication stress response to optimize cancer therapy. Nat Rev Cancer. 2023;23(1):6-24. doi: 10.1038/s41568-022-00518-6. PubMed PMID: 36323800; PMCID: PMC9789215.

8.  Ubhi T, Brown GW. Exploiting DNA Replication Stress for Cancer Treatment. Cancer Res. 2019;79(8):1730-9. doi: 10.1158/0008-5472.CAN-18-3631. PubMed PMID: 30967400.

9.  Golkowski M, Lius A, Sapre T, Lau HT, Moreno T, Maly DJ, Ong SE. Multiplexed kinase interactome profiling quantifies cellular network activity and plasticity. Mol Cell. 2023;83(5):803-18 e8. doi: 10.1016/j.molcel.2023.01.015. PubMed PMID: 36736316.

10.  Golkowski M, Lau HT, Chan M, Kenerson H, Vidadala VN, Shoemaker A, Maly DJ, Yeung RS, Gujral TS, Ong SE. Pharmacoproteomics Identifies Kinase Pathways that Drive the Epithelial-Mesenchymal Transition and Drug Resistance in Hepatocellular Carcinoma. Cell Syst. 2020;11(2):196-207 e7. doi: 10.1016/j.cels.2020.07.006. PubMed PMID: 32755597; PMCID: PMC7484106.

11.  Fleuren ED, Zhang L, Wu J, Daly RJ. The kinome 'at large' in cancer. Nat Rev Cancer. 2016;16(2):83-98. doi: 10.1038/nrc.2015.18. PubMed PMID: 26822576.

12.  Ferguson FM, Gray NS. Kinase inhibitors: the road ahead. Nat Rev Drug Discov. 2018;17(5):353-77. doi: 10.1038/nrd.2018.21. PubMed PMID: 29545548.