In June 2025, the research team released first-in-human Phase I clinical trial data showing that the fourth-generation EGFR-targeted inhibitor HS-10375 demonstrated manageable safety and early antitumor activity in non-small cell lung cancer patients carrying the EGFR C797S mutation. This marks the first potential breakthrough direction for triple resistance after progression on Osimertinib. This major advancement has ignited new hope in the field of EGFR resistance research and provides timely background and real-world significance for the development of the EGFR-MutCell platform.
EGFR is a key signal transduction molecule involved in normal human cell proliferation and is located on chromosome 7 at region 7p12. Activation of its protein function occurs when growth factors secreted and regulated by the body, such as EGF and TGFα, bind to the extracellular receptor, triggering EGFR to form transmembrane dimers. The intracellular TK domain undergoes a biochemical reaction with ATP, converting ATP to ADP, and TK phosphorylation activates EGFR enzymatic activity.
In human cancer cells, EGF and EGFR promote tumor cell proliferation and migration through the EGFR-Ras/Raf/MEK/ERK and EGFR-PI3K/AKT pathways; localize EGFR to the nucleus to enhance cell proliferation; disrupt autophagosome activity; stimulate several matrix metalloproteinases that promote cancer invasion and metastasis; and reduce the mRNA abundance of tumor-suppressive transcription factors mediated by EGF.
At present, among EGFR resistance mechanisms, the most studied is the EGFR-C797S mutation. EGFR-positive patients typically develop resistance after 1 to 2 years of treatment with first- or second-generation EGFR-TKIs. The EGFR-T790M mutation is the primary resistance mutation, accounting for as much as 50 to 60 percent. After treatment with the third-generation EGFR-TKI AZD9291, resistance is also inevitable, with the C797S mutation being the dominant resistance mutation.
However, different intervention timings of AZD9291 lead to different C797S resistance mutation patterns.
1. When AZD9291 is used as a second-line treatment, meaning it is introduced after the emergence of the EGFR-T790M mutation, the resulting resistance mutation is mainly the EGFR-T790M-C797S mutation. T790M and C797S mutations coexist, appearing in either cis or trans configurations. In this scenario, treatment requires combination therapy with first- and third-generation EGFR-TKIs or monoclonal antibodies.
2. When AZD9291 is used as a first-line treatment, meaning it is introduced at the stage of early EGFR mutations, subsequent resistance mutations are mainly MET amplification and isolated EGFR-C797S mutations. Due to AZD9291 treatment, these cases are not accompanied by T790M mutations. In this situation, treatment with a first-generation TKI can reverse C797S resistance. If a secondary T790M mutation subsequently occurs, AZD9291 can be reused, allowing maximal cumulative survival benefit.
At present, there are extensive studies on resistance mechanisms following the use of third-generation EGFR-TKIs. Among NSCLC patients resistant to Osimertinib, approximately 14 to 24 percent are C797S-positive. With the widespread adoption of NGS, resistance mechanisms to third-generation EGFR-TKIs have been preliminarily summarized as shown below:
To gain deeper insight into the core role of EGFR mutations and progression in NSCLC, it is necessary to establish a series of in vitro mechanistic cell models covering its typical mutation combinations. Against this background, the EGFR-MutCell platform was developed, aiming to significantly improve the screening efficiency of EGFR mutations and the analysis of mutation mechanisms.
- EGFR-MutCell Platform Products and In Vitro Validation Data
- EGFR-MutCell Platform Products and In Vivo Validation Data
