A multicenter study has revealed that adding a MET gene inhibitor to standard chemotherapy and immunotherapy significantly enhances treatment response in small cell lung cancer (SCLC), offering new hope for patients facing one of the most aggressive forms of lung cancer. The research, led by the Hospital del Mar Research Institute in collaboration with the CIBERONC cancer research network, was published in Cell Reports Medicine and represents the culmination of more than ten years of research.
Addressing an Aggressive Disease
Small cell lung cancer accounts for only 15% of all lung cancers but carries a devastating prognosis, with a three-year survival rate of just 15%. The disease's rapid progression and late diagnosis typically exclude surgical options, leaving patients dependent on chemotherapy and immunotherapy combinations. However, SCLC is notorious for its ability to develop treatment resistance and metastasize quickly.
The study focused on the role of hepatocyte growth factor (HGF), which is linked to cell proliferation and survival, in the poor prognosis of SCLC and its resistance to treatment. "We observed that combining immunotherapy and chemotherapy with a MET inhibitor makes immunotherapy more effective, increasing both survival and tumor response in mouse models," said Dr. Edurne Arriola, lead author of the study and researcher in the Cancer Molecular Therapy Research Group at Hospital del Mar.
Superior Treatment Outcomes
The research team analyzed treatment responses across multiple groups in mouse models of small cell lung cancer. One group served as an untreated control, while others received chemotherapy alone, chemotherapy combined with anti-PD-L1 monoclonal antibody immunotherapy, or the triple combination including a MET inhibitor. The most impressive results emerged from the group receiving all three treatments.
Six out of nine tumors treated with the MET inhibitor combination showed complete response, representing a significant improvement over standard therapy. "This strategy slowed tumor growth and in some cases, completely suppressed it. When we analyzed survival and tumor progression, mice treated with the MET inhibitor had better survival outcomes," Dr. Arriola noted.
Mechanism of Action
The MET inhibitor's effectiveness stems from its ability to modify the tumor microenvironment rather than directly attacking cancer cells. When MET is inhibited, "the tumor microenvironment—which contributes to treatment resistance—changes, making it easier for immune system T cells, activated by immunotherapy, to act," Dr. Arriola explained. This mechanism facilitates the effectiveness of standard treatment by creating conditions more favorable for immune system activation.
Clinical Validation
The researchers validated their preclinical findings using human tumor samples, revealing that MET gene overexpression correlates with worse patient prognosis. In cases where MET is overexpressed, patients experience a tumor microenvironment that impairs immunotherapy effectiveness and contributes to greater treatment resistance. This pattern was observed with both immunotherapy and chemotherapy treatments.
Notably, approximately half of SCLC patients show MET overexpression, making this discovery particularly relevant for a substantial portion of the patient population. The consistent findings between mouse models and human samples strengthen the potential for clinical translation.
Future Clinical Development
The research team is now preparing to initiate clinical trials in SCLC patients. The planned study will evaluate whether adding the MET inhibitor after initial chemotherapy and immunotherapy, during the maintenance treatment phase with immunotherapy alone, can prevent tumor progression. This approach could potentially extend the benefits of the combination therapy while minimizing treatment burden during the maintenance phase.
