PIK3CA and p53 Mutations Promote 4NQO-Initated Head and Neck Tumor Progression and Metastasis in Mice.

Autor:	García-Carracedo D; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.; Department of Otolaryngology - Head and Neck Surgery, Columbia University Irving Medical Center, New York, New York., Cai Y; Department of Otolaryngology - Head and Neck Surgery, Columbia University Irving Medical Center, New York, New York., Qiu W; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.; Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, New York., Saeki K; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.; Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, New York., Friedman RA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.; Department of Biomedical Informatics, Columbia University Medical Center, New York, New York., Lee A; Department of Otolaryngology - Head and Neck Surgery, Columbia University Irving Medical Center, New York, New York., Li Y; Department of Genetics and Development, Columbia University Medical Center, New York, New York., Goldberg EM; Department of Genetics and Development, Columbia University Medical Center, New York, New York., Stratikopoulos EE; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York., Parsons R; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York., Lu C; Department of Genetics and Development, Columbia University Medical Center, New York, New York., Efstratiadis A; Biomedical Research Foundation, Academy of Athens, Athens, Greece., Philipone EM; Division of Oral and Maxillofacial Pathology, Columbia University College of Dental Medicine, New York, New York., Yoon AJ; Division of Oral and Maxillofacial Pathology, Columbia University College of Dental Medicine, New York, New York., Su GH; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York. gs2157@columbia.edu.; Department of Otolaryngology - Head and Neck Surgery, Columbia University Irving Medical Center, New York, New York.; Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, New York.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2020 Jun; Vol. 18 (6), pp. 822-834. Date of Electronic Publication: 2020 Mar 09.
DOI:	10.1158/1541-7786.MCR-19-0549
Abstrakt:	The PI3K signaling pathway is frequently mutated in head and neck squamous cell carcinoma (HNSCC), often via gain-of-function (GOF) mutations in the PIK3CA gene. Here, we present novel genetically engineered mouse models (GEMM) carrying a GOF allele Loxp-STOP-Loxp(LSL)-PIK3CA H1047R (E20) alone or in combination with heterozygous LSL - p53 +/R172H (p53) mutation with tissue-specific expression to interrogate the role of oncogenic PIK3CA in transformation of upper aerodigestive track epithelium. We demonstrated that the GOF PIK3CA mutation promoted progression of 4-nitroquinoline 1-oxide-induced oral squamous cell carcinoma (OSCC) in both E20 single mutant and E20/p53 double mutant mice, with frequent distal metastasis detected only in E20/p53 GEMM. Similar to in human OSCC, loss of p16 was associated with progression of OSCC in these mice. RNA-seq analyses revealed that among the common genes differentially expressed in primary OSCC cell lines derived from E20, p53, and E20/p53 GEMMs compared with those from the wild-type mice, genes associated with proliferation and cell cycle were predominantly represented, which is consistent with the progressive loss of p16 detected in these GEMMs. Importantly, all of these OSCC primary cell lines exhibited enhanced sensitivity to BYL719 and cisplatin combination treatment in comparison with cisplatin alone in vitro and in vivo , regardless of p53 and/or p16 status. Given the prevalence of mutations in p53 and the PI3K pathways in HNSCC in conjunction with loss of p16 genetically or epigenetically, this universal increased sensitivity to cisplatin and BYL719 combination therapy in cancer cells with PIK3CA mutation represents an opportunity to a subset of patients with HNSCC. IMPLICATIONS: Our results suggest that combination therapy of cisplatin and PI3K inhibitor may be worthy of consideration in patients with HNSCC with PIK3CA mutation. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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