Targeted depletion of PIK3R2 induces regression of lung squamous cell carcinoma.
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.
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Universidad Autónoma de Madrid, Cantoblanco, Madrid.
Jesús
J
Vallejo-Díaz
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Universidad Autónoma de Madrid, Cantoblanco, Madrid.
Manuel
M
Olazabal-Morán
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Universidad Autónoma de Madrid, Cantoblanco, Madrid.
Ariel E
AE
Cariaga-Martínez
Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), Pamplona, Spain.|Navarra Health Research Institute (IDISNA), University of Navarra, Pamplona, Spain.|Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.
María J
MJ
Pajares
Department of Animal Medicine and Surgery, School of Veterinary Medicine, Complutense University of Madrid, Spain.
Juana M
JM
Flores
Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), Pamplona, Spain.|Navarra Health Research Institute (IDISNA), University of Navarra, Pamplona, Spain.|Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona, Spain.
Ruben
R
Pio
Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), Pamplona, Spain.|Navarra Health Research Institute (IDISNA), University of Navarra, Pamplona, Spain.|Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.
Luis M
LM
Montuenga
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Universidad Autónoma de Madrid, Cantoblanco, Madrid.
Ana Clara
AC
Carrera
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D047368:Tumor Burden; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; C560566:phosphoinositol-3 kinase regulatory subunit 2, human
PI3K pathway; PIK3R2; SQCC; lung cancer; targeted therapy