Therapeutic targeting of KMT2D mutant lung squamous cell carcinoma through RTK-RAS signaling inhibition
Inventors
Wong, Kwok-kin • Pan, Yuanwang • Han, Han • Zhang, Hua
Assignees
Publication Number
US-12336988-B2
Publication Date
2025-06-24
Expiration Date
2042-09-27
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Abstract
Provided is a method for treatment of lung squamous cell carcinoma (LUSC) by administering to an individual in need of treatment one or more inhibitors of the RTK-Ras signaling pathway. The LUSC cells may carry a mutation in a KMT2D gene. The inhibitors of the RTK-Ras signaling pathway are SHP2 inhibitors or epidermal growth factor receptor (EGFR) inhibitors. Combinations of the SHP2 inhibitors and EGFR inhibitors can be used.
Core Innovation
The invention provides a method for the treatment of lung squamous cell carcinoma (LUSC) by administering one or more inhibitors of the RTK-Ras signaling pathway to individuals in need of treatment, with particular emphasis on those whose LUSC cells carry a mutation in the KMT2D gene. The inhibitors may include SHP2 inhibitors and epidermal growth factor receptor (EGFR) inhibitors, either administered individually or in combination. This approach is based on data showing that KMT2D mutation is an oncogenic driver for LUSC and that KMT2D loss activates RTK-Ras signaling, rendering KMT2D−/− cells selectively sensitive to RTK-Ras signaling inhibition.
The problem addressed by the disclosure is the lack of effective targeted therapies for LUSC, which remains a major subtype of lung cancer with few actionable driver mutations and limited available treatment options. Previous targeted therapies have shown very limited clinical benefits, and there are no approved targeted therapies for LUSC. There is an urgent unmet need to explore actionable driver mutations and develop effective therapeutics for this patient population.
This disclosure demonstrates that identifying patients with KMT2D mutations enables the selection of those who are suitable candidates for therapy with SHP2 and/or EGFR inhibitors. The method comprises identifying the presence of KMT2D mutation in the lung tumor tissue of patients and administering a therapeutic agent that inhibits RTK-Ras signaling. The approach is supported by findings that KMT2D loss drives LUSC formation through activating RTK-Ras signaling, and that KMT2D-mutant LUSC cells exhibit hypersensitivity to inhibition of this pathway.
Claims Coverage
There is one independent claim relating to the method of treating LUSC characterized by a KMT2D loss of function mutation with specific combinations of RTK-Ras signaling pathway inhibitors.
Method of treating LUSC with KMT2D loss of function using a combination of afatinib and a SHP2 inhibitor
The method entails administering to an individual diagnosed with lung squamous cell carcinoma (LUSC), in whom a KMT2D loss of function mutation is identified prior to treatment, a combination of inhibitors of the RTK-Ras signaling pathway. - The combination specifically comprises afatinib and one of SHP099 or TNO155. - The diagnosis of LUSC and the identification of the KMT2D loss of function mutation in carcinoma cells must be established prior to treatment. - The administration involves the use of these agents in combination for the treatment of the individual in need.
The claims primarily cover a method of treating LUSC patients bearing KMT2D loss of function mutations with a combination of specific inhibitors targeting the RTK-Ras signaling pathway, with afatinib and either SHP099 or TNO155 comprising the inventive combination.
Stated Advantages
The method selectively targets KMT2D-mutant LUSC cells, which are shown to be hypersensitive to RTK-Ras pathway inhibition.
Combining SHP2 and EGFR inhibitors, such as SHP099 and afatinib, leads to greater tumor growth inhibition and prolonged survival compared to monotherapies or standard chemotherapy in preclinical models.
The invention addresses an urgent unmet need for effective targeted therapies in LUSC patients, particularly those with KMT2D mutations.
Documented Applications
Treatment of individuals diagnosed with lung squamous cell carcinoma (LUSC) who carry a KMT2D loss of function mutation, by administering combinations of RTK-Ras pathway inhibitors including afatinib and SHP2 inhibitors.
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