On July 15, 2025 Researchers at Korea University reported the protein kinase WEE1 as a key driver of this resistance (Press release, Korea University, JUL 15, 2025, View Source [SID1234654389]). They discovered that, outside its traditional role in the cell nucleus as tumor suppressor, cytoplasmic WEE1 fosters tumor growth and immune evasion by enhancing AKT hyperactivation. Targeting WEE1 with clinically available inhibitors may re-sensitize tumors to immunotherapy, offering new hope for treatment-resistant cancer patients.

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Immune checkpoints are regulatory proteins that prevent the immune system from attacking healthy tissues. Some cancer cells exploit these checkpoints to avoid immune detection. Immune checkpoint blockade (ICB)—a therapy that uses antibodies to block these deceptive signals—can unleash the immune system to destroy cancer.

However, a major challenge in oncology remains: why do some tumors resist ICB?

In a landmark study, researchers from Korea University have discovered a surprising answer: the protein WEE1, traditionally known as a cell cycle regulator and tumor suppressor, can paradoxically drive immune resistance when located in the cytoplasm of cancer cells.

Highlighting the significance of this achievement, Professor Tae Woo Kim from the Department of Biochemistry and Molecular Biology at Korea University College of Medicine, Seoul, Republic of Korea reveals, "Our findings uncover a non-canonical oncogenic mechanism of cytoplasmic WEE1 and provide a proof of principle that targeting WEE1 is an appealing combinational strategy to overcome refractory tumor to ICB therapy." This study was published in Volume 13, Issue 6 of Cancer Immunology Research journal on June 04, 2025.

RNA samples were obtained from patients with metastatic melanoma and non–small cell lung cancer who were undergoing ICB treatment. These patients were categorized as responders and non-responders, and their transcriptomic signatures were analyzed to understand WEE1 expression levels. The team found that WEE1 expression was significantly elevated in non-responders, correlating with poor prognosis, high tumor proliferation, and cancer stem cell (CSC)-like features.

Mechanistically, the transcription factor NANOG upregulates WEE1. Once phosphorylated by AKT, WEE1 relocates from the nucleus to the cytoplasm, where it activates the HSP90A–TCL1A–AKT loop, sustaining AKT hyperactivation.

Elucidating the molecular mechanism, Dr. Hyo-Jung Lee, the first author of the study, explains, "WEE1 is phosphorylated by AKT and then translocated in the cytosol, in which it phosphorylates HSP90A, consequently enhancing chaperon activity of HSP90A toward TCL1A, an AKT coactivator. Subsequently, stabilization of TCL1A results in an increase of its proteins levels, leading to amplification of the WEE1/HSP90A1/TCL1A/AKT auto-loop that promotes immune-refractory phenotypes and CSC-like properties of tumor cells."

Importantly, this study reveals the paradoxical role of cytoplasmic WEE1. While its canonical function involves DNA repair and tumor suppression in the nucleus, its non-canonical cytoplasmic role promotes tumor progression and immune resistance. These findings underscore the potential of WEE1 expression levels as predictive biomarkers for selecting patients who may benefit from ICB combination therapies.

Discussing the therapeutic implications of WEEI inhibitors, Prof. Kim comments, "Importantly, inhibiting WEE1 with a clinically relevant drug, adavosertib (AZD1775), sensitizes NANOG+ immune-refractory tumors to ICB and reinvigorates antitumor immunity via abrogating the autoamplifying loop triggered by AKT-dependent cytoplasmic WEE1."

This proof-of-concept study may also extend to other cell cycle regulators with similar dual functions, such as p21, p27, and CHK1, thereby broadening the landscape of therapeutic targets and paving the way for the development of novel treatment strategies.

Reference

Title of original paper:

Cytoplasmic WEE1 Promotes Resistance to PD-1 Blockade

Through Hyperactivation of the HSP90A/TCL1/AKT Signaling Axis in NANOGhigh Tumors

Journal:

Cancer Immunology Research

DOI:

10.1158/2326-6066.CIR-24-0379

On July 15, 2025 Akeso, Inc. (9926.HK) ("Akeso" or the "Company") reported that the first patient has been successfully enrolled in the registration Phase III clinical trial (AK112-312/HARMONi-GI6) of ivonescimab in first-line treatment for advanced metastatic colorectal cancer (mCRC) (Press release, Akeso Biopharma, JUL 15, 2025, View Source [SID1234654388]).

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This randomized, controlled, multi-center Phase III clinical trial for first-line treatment of mCRC is one of the company’s key initiatives to address the significant unmet clinical need worldwide with ivonescimab.

Colorectal cancer remains the third most common cancer globally and the second leading cause of cancer-related deaths. In 2022, over 1.9 million new cases were reported, with approximately 904,000 deaths. Of these, about 95% of mCRC cases are classified as microsatellite stable (MSS) or proficient mismatch repair (pMMR), which traditionally show poor responses to immunotherapy and the tumors are often referred to as an "immune desert."

For first-line treatment of MSS/pMMR-type mCRC, which represents up to 95% of cases, several PD-1/L1 inhibitors have been explored in multiple international studies. However, the efficacy has been limited, and as of now, no first-line immunotherapy has been approved globally for patients with pMMR/MSS-type mCRC.

Chemotherapy combined with targeted therapies (such as bevacizumab, cetuximab, etc.) remains the standard first-line treatment for mCRC, though its overall efficacy is limited, with a five-year survival rate for advanced patients of less than 20%. Bevacizumab is the most well-established and clinically impactful treatment in the mCRC space. It is also one of the core indications of bevacizumab.

At the 2024 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, Professor Yanhong Deng from the Sixth Affiliated Hospital of Sun Yat-sen University, presented promising Phase II efficacy data of ivonescimab in combination with chemotherapy for first-line treatment of MSS/pMMR-type mCRC.

The combination of ivonescimab with FOLFOXIRI demonstrated compelling anti-tumor activity in this hard to treat patient population, with an overall response rate (ORR) of 81.8% and a disease control rate (DCR) of 100%. After a median follow-up of 9 months, the median progression-free survival (mPFS) was not reached, with a 9-month PFS rate of 81.4%. Regardless of KRAS/BRAF mutation status, patients can benefit from ivonescimab combination therapy.

The results published at the 2024 ESMO (Free ESMO Whitepaper) suggest that ivonescimab may offer a significant improvement over existing treatment options for MSS/pMMR mCRC patients. The Phase III trial AK112-312/HARMONi-GI6 can potentially further validate the clinical benefits of ivonescimab in this setting, offering a novel first-line immunotherapy treatment option for patients with advanced mCRC.

On July 15, 2025 Senhwa Biosciences, Inc. (TPEx: 6492), a new drug development company focusing on first-in-class therapeutics for oncology, rare diseases, and infectious diseases, reported that its new drug Pidnarulex (CX-5461) has been selected by the U.S. National Cancer Institute (NCI) as part of a five-year cancer research program (Press release, Senhwa Biosciences, JUL 15, 2025, View Source [SID1234654387]). The first patient in the monotherapy clinical trial for advanced solid tumors has been successfully enrolled at the NIH Clinical Center in Bethesda, Maryland, USA.

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The NCI will fund the full cost of the clinical trial—estimated at approximately USD 4.8 million. In addition to this initial monotherapy trial, three other cutting-edge clinical studies led and sponsored by NCI are in progress. These include combination therapies with immunotherapy, antibody-drug conjugates (ADCs), and a monotherapy study targeting MYC-driven lymphomas. IND submissions and patient enrollment for these additional studies are expected to begin shortly.

Senhwa’s broad collaboration with the NCI not only highlights the innovative potential of CX-5461 as a first-in-class molecule targeting novel cancer mechanisms, but also reflects international recognition of Taiwan’s biotechnology achievements. This strengthens the company’s visibility and strategic position on the global stage in oncology drug development.

Trial Objectives and Research Focus
The first trial in the NCI program will investigate CX-5461 as a single agent in patients with and without homologous recombination deficiency (HRD) gene mutations, evaluating its ability to induce the Rad51 response. The study also aims to identify additional biomarkers associated with synthetic lethality to help define patient populations more likely to respond to treatment and potentially expand its clinical indications. The trial plans to enroll 40 patients, with allocated resources including clinical site operations, pharmacokinetic (PK) and biomarker analyses, as well as execution costs such as regulatory compliance, data management, and electronic platform infrastructure. With full financial support from NCI, the trial is expected to save the company an estimated USD 4.8 million in clinical development costs, significantly reducing the R&D burden and accelerating the advancement of CX-5461.

CX-5461 – A First-in-Class Investigational Drug
CX-5461 is a first-in-class small molecule drug with a unique mechanism of action. It acts by selectively targeting and stabilizing G-quadruplexes (G4s), preventing their unwinding and triggering replication-dependent DNA damage, ultimately resulting in cancer cell apoptosis. The frequent presence of G4 structures in tumors, especially in transcriptionally active genes, implies their potential functional involvement in the development of cancer. By targeting G4s and triggering DNA damage in cancer cells, Pidnarulex (CX-5461) emerges as a potential therapeutic candidate with significant promise across multiple cancer indications.

Growing Cancer Drug Market and the Need for Combination Therapies
With global cancer incidence on the rise, particularly among younger populations, the market for oncology drugs continues to expand. Demand for immunotherapies—which activate the human immune system to fight cancer—remains strong. According to the latest report by Grand View Research, Inc., the global cancer immunotherapy market is projected to reach USD 224.3 billion by 2030, with a compound annual growth rate (CAGR) of 8.3% from 2024 to 2030. However, current immunotherapies benefit only around 20–25% of patients, creating an urgent need for combination therapies that modulate multiple pathways within the tumor microenvironment to enhance treatment efficacy.

Senhwa is highly optimistic about its future clinical plans under the leadership of the NCI, particularly the combination studies involving CX-5461 and immunotherapies. These trials may help overcome the limitations of current immunotherapies and expand their benefit to a broader cancer patient population.

On July 16, 2025 Imugene Limited (ASX: IMU), a clinical-stage immunooncology company, reported that it will hold a webinar presentation to update shareholders, investors and other interested parties on the latest data from its Phase 1b trial of azer-cel (Press release, Imugene, JUL 15, 2025, https://mcusercontent.com/e38c43331936a9627acb6427c/files/2de571a9-dbf5-1f0e-44f9-d5bfdd998ae5/Azer_cel_new_data_Webinar.pdf [SID1234654386]).

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The webinar will be hosted by Executive Chairman Paul Hopper, CEO & Managing Director Leslie Chong, and Chief Medical Officer Dr John Byon.

The webinar will be held at 11am AEST on Thursday 17 July 2025.

Shareholders, investors and interested parties can register to attend the webinar at the following link: View Source

Shareholders are encouraged to submit questions for the webinar in advance via email at: [email protected]

A recording will be available at the above link shortly after the conclusion of the live session, and the replay will also be available via the Company’s website and social media channels.

On July 15, 2025 Lantern Pharma Inc. (NASDAQ: LTRN), a pioneering artificial intelligence (AI) company transforming oncology drug discovery and development, reported the launch of an innovative AI-powered module within its proprietary RADR platform, designed to predict the activity and efficacy of combination regimens involving DNA-damaging agents (DDAs) and DNA damage response inhibitors (DDRis) in clinical cancer treatment (Press release, Lantern Pharma, JUL 15, 2025, View Source [SID1234654385]). With the global market for combination cancer therapies projected to exceed $50 billion by 2030, growing at a CAGR of 8.5%, this module represents a significant advancement in precision oncology, enabling faster, more cost-effective development of tailored therapeutic regimens. Leveraging this AI-driven framework, Lantern Pharma has successfully architected and achieved FDA clearance for a Phase 1B/2 clinical trial in triple-negative breast cancer (TNBC), focusing on a novel DDA-DDRi combination regimen with promising preclinical efficacy.

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In a peer-reviewed study published in Frontiers in Oncology, Clinical outcomes of DNA-damaging agents and DNA damage response inhibitors combinations in cancer: a data-driven review, Lantern Pharma researchers systematically analyzed 221 DDA-DDRi combination-arm clinical trials, involving 22 DDAs and 46 DDRis, to develop this module. The study categorized DDAs into eight subclasses (e.g., alkylating agents, interstrand cross-linkers) and DDRis into 14 subclasses (e.g., PARP, ATR, WEE1 inhibitors). From these, 89 trials with interpretable outcomes were scored for clinical effectiveness, safety, and biomarker-driven responses, providing a robust dataset to train the AI module.1

Transforming Cancer Combination Therapy Development

The new AI module represents a paradigm shift in precision oncology, leveraging machine learning to predict which drug combinations will be most effective for specific patient populations while minimizing toxicity risks. This data-driven approach has already demonstrated its value by successfully guiding the design of Lantern’s FDA-cleared Phase 1B/2 clinical trial combining LP-184 with olaparib in triple-negative breast cancer (TNBC).

"This AI-powered module is a transformative step in our mission to deliver personalized cancer treatments," said Panna Sharma, CEO & President of Lantern Pharma. "By leveraging our RADR platform to analyze complex multi-omics and clinical trial data, we identified optimal DDA-DDRi combinations that guided the development of our TNBC trial. We believe this approach could reduce combination therapy development timelines and costs by one-third compared to traditional methods."

The module integrates genomic, transcriptomic, and clinical data to predict synergistic drug interactions, optimize therapeutic outcomes, and identify biomarker-defined patient subpopulations likely to respond to specific combinations. This data-driven approach directly informed the design of Lantern’s FDA-cleared Phase 1B/2 trial in TNBC for LP-184 and olaparib, with potential to improve response rates and reduce toxicity.

Key insights from the study powering the AI module include:

Non-PARP Inhibitor Promise: Non-PARP DDRi combinations, particularly WEE1 inhibitors like adavosertib with platinum agents, showed an 80% positive outcome rate in interstrand cross-linker trials, with strong efficacy in TP53-mutated cancers, directly informing future trial design.
Biomarker-Driven Success: Biomarkers such as TP53 mutations and HRD signatures were critical predictors of response, enabling patient stratification to maximize efficacy.
Toxicity Mitigation: The use of novel formulations like liposomal doxorubicin in combination regimens reduced cardiotoxicity, providing a safer backbone for combination strategies.
Emerging Trends: The analysis emphasizes the patterns in treatment effectiveness, safety, and emerging trends across various cancer types and discusses the potential of biomarkers to guide treatment selection and improve patient outcomes.
The module’s multi-agentic framework integrates specialized AI agents for data aggregation, drug classification, predictive modeling, biomarker identification, and optimization, creating a dynamic system that is planned to evolve along with new data. The system’s continuous learning capability ensures adaptability, enabling Lantern to refine regimens and accelerate future trials across diverse cancer indications. The company is exploring licensing and commercialization opportunities to expand the application of this technology, further revolutionizing combination therapy development.