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Targeted depletion of PIK3R2 induces regression of lung squamous cell carcinoma
Jesús Vallejo-Díaz1, Manuel Olazabal-Morán1, Ariel E Cariaga-Martínez1
1Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Universidad Autónoma de Madrid, Cantoblanco, Madrid.
Abstract:
Oncogenic mutations in the PI3K/AKT pathway are present in nearly half of human tumors. Nonetheless, inhibitory compounds of the pathway often induce pathway rebound and tumor resistance. We find that lung squamous cell carcinoma (SQCC), which accounts for ~20% of lung cancer, exhibits increased expression of the PI3K subunit PIK3R2, which is at low expression levels in normal tissues. We tested a new approach to interfere with PI3K/AKT pathway activation in lung SQCC. We generated tumor xenografts of SQCC cell lines and examined the consequences of targeting PIK3R2 expression. In tumors with high PIK3R2 expression, and independently of PIK3CA, KRAS, or PTEN mutations, PIK3R2 depletion induced lung SQCC xenograft regression without triggering PI3K/AKT pathway rebound. These results validate the use PIK3R2 interfering tools for the treatment of lung squamous cell carcinoma.
Insights
Targeting PIK3R2 in lung squamous cell carcinoma (SQCC) offers a new treatment. Depleting PIK3R2 shrinks tumors without causing pathway rebound, suggesting a promising therapeutic strategy for this cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The PI3K/AKT pathway is frequently altered in human cancers.
- Inhibitors of this pathway often lead to resistance and pathway rebound.
- Lung squamous cell carcinoma (SQCC) shows increased PIK3R2 expression.
Purpose of the Study:
- To investigate a novel therapeutic approach targeting PIK3R2 in lung SQCC.
- To evaluate the efficacy of PIK3R2 depletion in preclinical models of SQCC.
Main Methods:
- Generation of lung SQCC tumor xenografts.
- Targeting and depletion of PIK3R2 expression in xenografts.
- Assessment of tumor regression and PI3K/AKT pathway activity.
Main Results:
- PIK3R2 depletion led to significant regression of lung SQCC xenografts.
- This effect was observed independently of common mutations (PIK3CA, KRAS, PTEN).
- Targeting PIK3R2 did not induce PI3K/AKT pathway rebound.
Conclusions:
- PIK3R2 is a potential therapeutic target in lung squamous cell carcinoma.
- PIK3R2 interfering tools represent a promising strategy for treating SQCC.
- This approach overcomes common resistance mechanisms associated with PI3K/AKT pathway inhibition.
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