A research team led by Professor Xiang David Li from the Department of Chemistry at The University of Hong Kong (HKU), in collaboration with researchers from the Shenzhen Bay Laboratory and Tsinghua University, has made a breakthrough in epigenetic drug discovery. The team has successfully developed a first-in-class chemical inhibitor that precisely and selectively targets the ATAC complex, a critical cellular “switch operator” that activates tumour-promoting genes, opening a novel therapeutic avenue for non-small cell lung cancer (NSCLC). The findings were recently published in the top-tier journal Nature Chemical Biology, and multiple international patent applications have been filed.
Histone Modifications as Genetic Switches in Our Cells
Inside human cells, DNA is wrapped around protein structures called histones to form chromatin. Chemical modifications on histones function like genetic “switches”, determining whether genes are turned on or remain silent. Among these modifications, histone acetylation is one of the most important “on” switches that activate gene expression. This modification is catalysed by enzyme complexes known as histone acetyltransferases (HATs).
The ATAC complex is one such HAT complex and plays a pivotal role in activating genes involved in cell growth and DNA replication. In cancers such as NSCLC, the ATAC complex becomes overactive, inappropriately flipping the “on” switch for numerous cancer-driving genes, fuelling uncontrolled tumour growth and spread. However, selectively inhibiting ATAC without disrupting other essential cellular complexes has remained a challenge in drug development.
Precisely Targeting a Unique Component of ATAC
Previous drug-development efforts focused on inhibiting GCN5, the catalytic subunit responsible for histone acetylation within ATAC. Nevertheless, GCN5 is also shared by several other HAT complexes, meaning that blocking it would inadvertently interfere with normal cellular functions and lead to significant side effects. To address this challenge, Professor Li’s team devised an innovative strategy targeting YEATS2, a protein subunit specific to the ATAC complex.
Using structure-guided design, the researchers developed a potent and highly selective inhibitor of YEATS2, named LS-170. This inhibitor specifically binds to the acetyl-lysine recognition domain of YEATS2, preventing it from anchoring the ATAC complex to chromatin. Consequently, the complex is displaced from its target genomic regions, leading to a significant reduction in local histone acetylation and the “off” switching of oncogenes in NSCLC.
Tumour suppression in vivo — In animal models, LS-170 treatment significantly reduced tumour volume, demonstrating its strong anti-cancer potential. (Image adapted from the relevant journal.)
Strong Suppression of Tumour Growth and Metastasis
In NSCLC cell lines and animal models, LS-170 demonstrated strong efficacy in suppressing tumour growth and metastasis. Notably, the YEATS2 gene is frequently amplified in multiple solid tumours—including lung, ovarian, and pancreatic cancers—suggesting that this targeted strategy may hold broader therapeutic potential beyond lung cancer.
This study represents the first chemical approach to precisely decode the function of a specific HAT complex, revealing ATAC's distinct role in maintaining gene expression programs in cancer. It also offers new insights for developing other complex-specific epigenetic drugs for human diseases.
“In this work, we didn’t just create a potent and highly specific inhibitor that can suppress tumours, we also uncovered a novel strategy to target just one epigenetic complex out of several that share the same enzyme core. This approach opens up exciting possibilities for developing highly selective, complex-specific drugs that could potentially revolutionise treatments for human diseases,” said Professor Xiang Li, one of the corresponding authors of the paper.
About the Research Team:
The interdisciplinary collaboration was led by Professor Xiang David LI (HKU Chemistry), together with Professor Weiping WANG (HKU Pharmacology and Pharmacy), Researcher Xin LI (Shenzhen Bay Laboratory), and Professor Haitao LI (Tsinghua University). Co-first authors included Dr Sha LIU, Dr Yin Qiao WU, Dr Jinzhao LIU, and Dr Xinyi YAO.
Lung cancer is one of the most common cancers in Hong Kong and carries the highest mortality rate, not only locally but also globally. Professor Rina Hui, Director of the Centre for Cancer Medicine at the University of Hong Kong (HKU), said that cancer treatment is advancing at an unprecedented pace, with new breakthroughs emerging almost every fortnight. These include antibody-drug conjugates (ADCs) that are often referred to as "smart chemotherapy", T-cell engagers, and bispecific antibodies, which combine two different antibodies.
With such rapid progress, the curriculum at HKU’s Li Ka Shing Faculty of Medicine (HKUMed) needs to keep pace. About a year and a half ago, the faculty launched an eight-month integrated cancer medicine course to equip medical students with the latest clinical cancer technologies.
Professor Rina Hui, Director of the Centre for Cancer Medicine at the University of Hong Kong (HKU), Photo by Bastille Post
Professor Hui told Bastille Post that, in Hong Kong, besides lung cancer, the most common cancers include colorectal, breast, and prostate cancer. But lung cancer remains the biggest challenge, since its mortality rate is higher than the other three combined.
She said that besides smoking, other risk factors for lung cancer include second‑hand smoke, the second largest contributor, as well as family history, air pollution, kitchen fumes, occupational exposure (e.g., asbestos and radon), and prior radiotherapy. Smoking, however, remains by far the leading cause.
EGFR Mutations Common in HK Lung Adenocarcinoma
Professor Hui noted that Hong Kong's smoking rate has dropped to 8.5%, according to the latest figures released by the Health Bureau in April. While smoking‑related cancers like small cell lung cancer and squamous cell carcinoma are declining, lung adenocarcinoma is increasing, with half of patients carrying EGFR mutations. "Knowing the cancer type and genetic status is the first step for effective treatment," she said.
She also emphasised that the earlier one quits smoking, the lower the risk of getting cancer. "Quitting need not be abrupt. Nicotine patches and chewing gum can serve as supportive aids. The essential step is to discard all cigarettes, eliminate temptation, and reframe quitting as a long‑term health investment," she advised.
Professor Hui suggested that lung cancer screening is essential for high‑risk individuals. Photo source: reference image
Lung Cancer Screening: Essential for High‑Risk Individuals
Last year, the government announced plans to commission local universities to conduct AI‑assisted lung cancer screening. Professor Hui said that HKU and CUHK are currently running relevant trials, given their importance.
"High‑risk people, like those aged 50 to 75, heavy smokers (30 pack‑years), and those exposed to second‑hand smoke, should get screened regularly," she said. "Taiwan offers a noteworthy approach, where they screen non‑smokers with a family history of lung cancer."
She acknowledged that free lung cancer screening for every individual in Hong Kong is unlikely to be feasible at this stage, due to the high costs involved. However, screening could be carried out through collaboration between the government and private healthcare providers, targeting high‑risk groups. "As I tell my patients, getting screened is like saving up to pay taxes. You're actually gaining in the long run. Early detection means better outcomes and lower treatment costs."
She said that lung cancer treatment regimens are becoming increasingly advanced. "Patients with genetic alterations can use targeted therapies; those without can benefit from immunotherapy, and survival rates have improved significantly." However, she also pointed out that lung cancer remains the world's "number one cancer killer", underscoring the urgent need for continued related research and clinical trials.
Recognising the rapid evolution of cancer treatment, HKUMed has launched an eight‑month integrated cancer medicine course starting in October 2024. Photo source: reference image
New Course to Train Future Doctors
Recognising the rapid evolution of cancer treatment, HKUMed has launched an eight‑month integrated cancer medicine course starting in October 2024, which is delivered in six cohorts per year, ensuring that future doctors stay abreast of the latest developments. "We bring together surgeons, researchers, public health experts, oncologists (including medical oncologists and radiation oncologists), pathologists, and radiologists to teach medical students the basics of immunotherapy, targeted therapies, smart chemotherapy, and radiation, so that no matter what field they go into, they'll be able to handle cancer patients when they see them," she said.
New Cancer Treatments Bring New Hope
Beyond well‑established immunotherapy, Professor Hui highlighted emerging treatments:
One is called Antibody‑Drug Conjugate (ADC), often referred to as "smart chemotherapy" or "missile‑guided chemotherapy." "The antibody carries the chemotherapy drug, entering cancer cells with precision like a missile. When the linker dissolves, it releases the drug directly into the cancer cells, killing them effectively," she explained.
She noted that ADCs have now been proven to benefit patients with stage IV metastatic cancer. Clinical trials are currently combining these drugs with immunotherapy, and data have already shown effectiveness in early‑stage triple‑negative breast cancer patients.
Another future trend in cancer treatment is bispecific antibodies, which combine two different antibodies with fewer side effects and a synergistic effect. For example, VEGF bispecific antibodies combine the dual mechanisms of immune checkpoint inhibitors and anti‑angiogenic therapy, and have already shown effectiveness in cancers such as lung and breast cancer. Combining two targeted drugs also results in fewer side effects and better treatment outcomes for lung cancer patients.
T‑Cell Engagers: A Breakthrough for Small Cell Lung Cancer
Professor Hui also mentioned a new treatment trend called T-cell engagers. "For example, a therapy targeting DLL3 on the surface of small cell lung cancer cells — on one side, it targets DLL3, and on the other side, it attracts the immune system's T-cells, which act like soldiers attacking the cancer cells together. This type of drug is already on the market and has been shown to improve overall survival in extensive-stage small-cell lung cancer. Clinical trials are currently exploring its use in first-line treatment and for stage III patients," she explained.
However, she pointed out that targeted therapy remains a future priority. Since many cancers occur due to genetic alterations, if the genes driving cancer growth can be identified, targeted medications can be utilized and show improved therapeutic efficacy across various cancers. For example, 60% to 70% of breast cancers are hormone receptor-positive, and of those, 30% to 40% have PIK3CA gene mutations. "The corresponding targeted drugs are currently available in Hong Kong, but they are expensive. There is now a phase III clinical trial in which patients can use this type of medication for free, and may even have access to better new drugs. However, patients need to undergo genetic sequencing to confirm whether they have the corresponding genetic mutation before they can participate in the relevant trial," she said.
According to Professor Hui, since many cancers occur due to genetic alterations, if the genes driving cancer growth can be identified, targeted medications can be utilized and show improved therapeutic efficacy across various cancers. Photo by Bastille Post
