About

Lee Zou is the George Barth Geller Distinguished Professor of Pharmacology and Cancer Biology at Duke University. He serves as the Chair of the Department of Pharmacology and Cancer Biology and is a member of the Duke Cancer Institute. His research focuses on pharmacology and cancer biology, contributing to the understanding of molecular mechanisms underlying cancer development and treatment. As a leading figure in his field, he is involved in advancing scientific knowledge through his role in academia and research at Duke University.

Research topics

• Genetics
• Cell biology
• Biology
• Virology
• Molecular biology
• Computational biology

Selected publications

• Targeted therapy-induced chromosomal instability dictates mitotic dependency on Aurora Kinase A

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-23

  article

  Abstract Targeted therapies eliminate cancer cells by inhibiting oncogenic signaling; however, tumor cells often evade cytotoxicity through proteomic and epigenetic reprogramming that enables survival. These adaptive responses may create collateral cellular stresses, such as DNA damage, that can be therapeutically exploited. When unresolved, DNA damage leads to chromosomal instability (CIN), a potential source of vulnerability. Whether KRAS inhibition induces DNA damage or CIN in KRAS -mutant non-small cell lung cancer (NSCLC) has not been established. Here, we show that the KRAS G12C inhibitor LY3499446 induces CIN in KRAS -mutant NSCLC cell lines. A targeted compound screen revealed that the extent of CIN induction by KRAS G12C inhibition strongly correlates with therapeutic synergy with the selective Aurora kinase A inhibitor LSN3321213. Mechanistically, KRAS G12C inhibition stabilizes cyclin B1 during mitosis through activation of mitotic ATR/ATM signaling. In the presence of Aurora Kinase A inhibition, cyclin B1 stabilization delays mitotic exit and diverts cell fate from mitotic slippage or division toward mitotic catastrophe. Together, our findings identify CIN as a predictive marker of response to combined KRAS G12C and Aurora Kinase A inhibition, providing mechanistic rationale to enhance the therapeutic window of AURKA inhibitors when used with targeted therapies.

  PublisherDOI

• SMARCAL1 is a targetable synthetic lethal therapeutic vulnerability in ATRX-deficient gliomas that use alternative lengthening of telomeres

  Neuro-Oncology · 2026-01-09 · 2 citations

  articleOpen access

  BACKGROUND: Approximately 10% of cancers achieve replicative immortality through a telomerase-independent mechanism of telomere maintenance, termed Alternative Lengthening of Telomeres (ALT). ALT is particularly prevalent in certain subtypes of malignant gliomas, such as IDH-mutant astrocytoma and pediatric glioblastoma, and frequently co-occurs with ATRX (ATRX chromatin remodeler) inactivating mutations. Although ALT is an adaptive mechanism through which cancer cells achieve proliferative immortality, the elevated levels of replication stress observed in ALT tumors constitute a potential therapeutic vulnerability. METHODS: Leveraging CRISPR/Cas9 screening data from the Cancer Dependency Mapping Project, coupled with patient-derived cell lines and xenografts, we identified SMARCAL1 as a novel synthetic lethal vulnerability in ATRX-deficient glioma models that engage ALT. Using complementary molecular assays for DNA damage, telomere maintenance, and telomeric replication stress, we define the mechanisms underlying cytotoxicity induced by SMARCAL1 depletion in ALT-positive glioma cells. RESULTS: Our data demonstrate the annealing helicase SMARCAL1 is a highly specific synthetical lethal vulnerability in cancers that use ALT. SMARCAL1 localizes to ALT-associated PML (Promyelocytic leukemia protein) bodies in ALT-positive glioma cell lines, including IDH-mutant astrocytomas. SMARCAL1 depletion, via doxycycline-induced RNAi, led to a hyperactivation of the ALT phenotype, high levels of DNA double-strand breaks in G2 phase, and cell death via mitotic catastrophe. In mice bearing intracranial xenografts derived from high-grade IDH-mutant astrocytoma, inducible SMARCAL1 depletion prolonged animal survival. CONCLUSIONS: Our findings demonstrate that the molecular processes orchestrating ALT-mediated telomere maintenance constitute a targetable synthetic lethal vulnerability that can be exploited by SMARCAL1 inhibition, thus supporting the future development of small molecule inhibitors of SMARCAL1 as anti-cancer therapeutics.

  PublisherDOI

• Abstract A013: Targeted therapy-induced chromosomal instability dictates mitotic dependency on Aurora Kinase A

  Cancer Research · 2026-03-05

  article

  Abstract Targeted therapies are designed to eliminate cancer cells by directly inhibiting oncogenic driver proteins. In addition to their primary inhibitory effects on oncogenic signaling, these agents frequently impose collateral cellular stresses, such as DNA damage. KRAS-targeted therapies, particularly KRAS G12C inhibitors (G12Ci), represent a major therapeutic advance but remain limited in efficacy. Previous reports of targeted therapy-induced DNA damage, including studies of TKIs and MAPK inhibitors, have primarily been based on cytotoxic dosing conditions. Far less is known about whether DNA damage can also be induced by targeted therapies in less sensitive cancer models, particularly under sublethal doses that better mimic clinical responses. Failure to repair DNA damage can lead to chromosomal instability (CIN) and chromosomal aberrations. CIN is widely recognized to promote tumor evolution by enhancing cellular plasticity and adaptability, thereby contributing to therapeutic resistance and metastatic progression. However, it remains unknown how KRAS G12C inhibition influences CIN and whether G12Ci-induced CIN might generate unique, exploitable vulnerabilities. In this study, we profiled 15 KRAS G12C-mutant NSCLC cell lines representing diverse mutational backgrounds. We treated these models with the KRAS G12Ci LY3499446 and comprehensively assessed their DNA damage responses, CIN phenotypes, and sensitivities to combination therapies with agents that perturb chromosomal stability. We observed heterogeneous induction of DNA damage and CIN across these cell lines. Notably, we identified the strongest correlation between G12Ci-induced CIN and synergistic interaction with the Aurora kinase A inhibitor (AURKAi) LSN3321213. Machine learning-based single-cell image tracking and DNA barcoding analyses revealed that AURKA inhibition alone causes mitotic arrest followed by mitotic slippage, allowing cells to evade death, whereas combined G12Ci and AURKAi treatment triggers catastrophic mitotic cell death. Mechanistically, we found that G12Ci stabilizes Cyclin B1 through mitotic activation of ATR/ATM DNA repair signaling, thereby prolonging mitotic arrest. Under conditions of combined inhibition of KRAS G12C and AURKA, in which Cyclin B1 degradation is impaired, cells fail to exit mitosis and undergo catastrophic cell death. Together, our findings identify CIN as a predictive marker of response to combined KRAS G12C and AURKA inhibition, providing mechanistic rationale to enhance the therapeutic window of AURKA inhibitors when used with targeted therapies. Citation Format: Chendi Li, Varuna Nangia, Melissa Vieira, Anahita Nimbalkar, Christopher J. Graser, Jeremy Chang, Mohammad U. Syed, Yi Shen, Radhika Koranne, Lee Zou, Sabrina L. Spencer, Aaron Hata. Targeted therapy-induced chromosomal instability dictates mitotic dependency on Aurora Kinase A [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A013.

  PublisherDOI

• ATM counteracts chromatin-bound cGAS during DNA replication

  Nature Cell Biology · 2026-04-29

  articleSenior author
  PublisherDOI

• ATR Safeguards Epithelial-to-Mesenchymal Transition by Countering R-loops and Enabling Transcription Reprogramming

  Journal of Clinical Investigation · 2026-01-22

  articleOpen accessSenior author

  Transitions of cancer cells between distinct cell states, which are typically driven by transcription reprogramming, fuel tumor plasticity, metastasis, and therapeutic resistance. Whether the transitions between cell states can be therapeutically targeted remains unknown. Here, using the epithelial-to-mesenchymal transition (EMT) as a model, we show that the transcription reprogramming during a cell-state transition induces genomic instability through R-loops and transcription-replication conflicts, and the cell-state transition cannot occur without the ATR kinase, a key regulator of the replication stress response. ATR inhibition during EMT not only increases transcription- and replication-dependent genomic instability but also disrupts transcription reprogramming. Unexpectedly, ATR inhibition elevates R-loop-associated DNA damage at the SNAI1 gene, a key driver of the transcription reprogramming during EMT, triggering ATM- and Polycomb-mediated transcription repression of SNAI1. Beyond SNAI1, ATR also suppresses R-loops and antagonizes repressive chromatin at a subset of EMT genes. Importantly, inhibition of ATR in tumors undergoing EMT reduces tumor growth and metastasis, suggesting that ATR inhibition eliminates cancer cells in transition. Thus, during EMT, ATR not only protects genome integrity but also enables transcription reprogramming, revealing that ATR is a safeguard of cell-state transitions and a target to suppress tumor plasticity.

  PublisherDOI

• Gap resection matters in BRCA mutant cancer

  Genes & Development · 2025-04-10 · 2 citations

  reviewOpen access1st authorCorresponding

  Cancer cells deficient in BRCA1/2 have impaired DNA repair, making them sensitive to PARP inhibitors (PARPis). In this issue of Genes & Development , Seppa and colleagues (doi:10.1101/gad.352421.124) investigated how BRCA1 protects single-stranded DNA gaps from nucleolytic processing. They showed that PARPi-induced gaps are rapidly resected by several exonucleases bidirectionally and filled by translesion synthesis. In BRCA1-deficient cells, gaps become larger and persistent due to excessive resection. These gaps do not convert to DNA double-stranded breaks (DSBs) via endonuclease activity but cause DSBs through replication fork collisions in a cell cycle-dependent manner. This research clarifies how BRCA1 loss contributes to PARPi sensitivity in BRCA mutant tumors.

  PublisherOA PDFDOI

• ZNF280A links DNA double-strand break repair to human 22q11.2 distal deletion syndrome

  Nature Cell Biology · 2025-06-01 · 2 citations

  articleOpen access
  PublisherOA PDFDOI

• Supplementary Figure S4 from A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors

  2025-01-06

  preprintOpen access

  <p>Figure S4. H-score of pre- and on-treatment biopsy stained with anti-SLFN11 antibody for each patient is shown. Patients from cohort 4 was not included in the analysis. Patients from T4 was not included in this analysis.</p>

  PublisherDOI

• Supplementary Figure S1 from A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors

  2025-01-06

  preprintOpen access

  <p>Figure S1: (A) Study schema. Patients were recruited into one of four cohorts based on NGS or IHC. Patients received twice-per week infusions of berzosertib at the recommended phase 2 dose. Paired biopsies were collected for cohorts 1 to 3 for translational studies. Six patients were allowed per cohort; however, patients could be replaced if paired biopsies were unsuccessful. *For cohort T3, gene alterations included: germline BRCA1/2 mutations, other homologous repair (HR) alterations (e.g., somatic BRCA1/2, BARD1, BRIP1, CDK12, CHEK2, FANCA, FANCC, FANCE, FANCF, FANCM, MRE11A, NBN, PALB2, RAD51B, RAD51C and RAD51D), MYC amplification, FBXW7 truncating or missense mutations, CCNE1 amplification, ARID1A mutations. (B) Kaplan-Meier plot showing Progression free survival of patients in each cohort</p>

  PublisherDOI

• Supplementary Table S1 from A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors

  2025-01-06

  supplementary-materialsOpen access

  <p>Representativeness of Study Participants</p>

  PublisherDOI

Recent grants

• Regulation of the ATR Checkpoint Kinase by DNA Damage

  NIH · $4.3M · 2006–2019

• Implications of the ATR Checkpoint Kinase in Radiation and Targeted Therapies

  NIH · $2.4M · 2015–2021

• Impacts of APOBECs on DNA replication, ATR checkpoint, and cancer therapy

  NIH · $1.5M · 2018–2023

Frequent coauthors

• Michael S. Lawrence

  98 shared

• Cyril H. Benes

  93 shared

• Rémi Buisson

  University of California, Irvine

  88 shared

• Antoine Simoneau

  Tango Therapeutics (United States)

  77 shared

• Li Lan

  Beijing Ditan Hospital

  75 shared

• Jian Ouyang

  MUSC Hollings Cancer Center

  71 shared

• Daniel A. Haber

  Harvard University

  66 shared

• Henning Willers

  Massachusetts General Hospital

  65 shared