KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Lung squamous cell carcinoma (LUSC) is a major lung cancer subtype with few effective treatments.
• KMT2D is frequently mutated in LUSC, but its oncogenic role is unclear.

Purpose of the Study:

• To investigate the function of KMT2D in LUSC development.
• To explore therapeutic strategies targeting KMT2D-mutated LUSC.

Main Methods:

• Utilized Kmt2d deletion in lung basal cell organoids and murine models.
• Analyzed chromatin landscape and gene expression changes.
• Investigated the efficacy of SHP2 and ERBB inhibitors in KMT2D-deficient models and patient-derived xenografts (PDXs).

Main Results:

• Kmt2d deletion induced LUSC formation.
• KMT2D loss upregulated receptor tyrosine kinases (EGFR, ERBB2) by repressing phosphatases, enhancing RTK-RAS signaling.
• Combined SHP2 and ERBB inhibition reduced tumor growth in KMT2D-deficient models and PDXs.

Conclusions:

• KMT2D is a critical epigenetic regulator in LUSC tumorigenesis.
• KMT2D deficiency creates a therapeutic vulnerability to RTK-RAS pathway inhibitors in LUSC.