RICTOR amplification identifies a subgroup in small cell lung cancer and predicts response to drugs targeting mTOR

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Small cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options.
• Currently, no targeted therapies exist for SCLC, highlighting an unmet clinical need.
• Genomic alterations are crucial drivers in cancer progression and therapeutic response.

Purpose of the Study:

• To investigate the translational potential of recurrent RICTOR amplification in SCLC.
• To determine the correlation between RICTOR copy number variation and protein expression.
• To assess the sensitivity of SCLC cells with RICTOR amplification to mTOR inhibitors.

Main Methods:

• Genomic analysis of a metastatic SCLC cohort to identify gene amplifications.
• Correlation analysis of RICTOR copy number variation (CNV) with protein expression.
• Cell growth assays and signaling pathway analysis to evaluate drug sensitivity.
• Chemotaxis and scratch wound assays to assess cell migration.

Main Results:

• RICTOR was the most frequently amplified gene (~14%) in SCLC, often co-amplified with FGF10 and IL7R.
• RICTOR copy number gain correlated with increased RICTOR protein expression.
• SCLC cells with RICTOR CN gain exhibited heightened sensitivity to mTOR inhibitors, particularly AZD2014.
• RICTOR amplification was associated with significantly decreased overall survival in SCLC patients (p = 0.021).

Conclusions:

• RICTOR amplification represents a potential therapeutic target in a subset of SCLC patients.
• Patients with RICTOR-amplified SCLC may benefit from mTORC1/2 inhibitor therapy.
• This finding identifies a clinically significant subgroup for targeted treatment strategies.