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Published on: April 22, 2019
PIK3CA and p53 Mutations Promote 4NQO-Initated Head and Neck Tumor Progression and Metastasis in Mice
Darío García-Carracedo1,2, Yi Cai2, Wanglong Qiu1,3
1Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.
Abstract:
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 (E20) alone or in combination with heterozygous LSL-p53 (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.
Insights
Genetically engineered mouse models reveal that PIK3CA mutations drive oral squamous cell carcinoma (OSCC) progression. Combination therapy with PI3K inhibitor BYL719 and cisplatin shows promise for HNSCC patients with PIK3CA mutations.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The PI3K signaling pathway, particularly the PIK3CA gene, is frequently mutated in head and neck squamous cell carcinoma (HNSCC).
- Gain-of-function (GOF) mutations in PIK3CA are common drivers in HNSCC, necessitating better understanding of their role in tumorigenesis.
Purpose of the Study:
- To investigate the role of oncogenic PIK3CA in the transformation of upper aerodigestive tract epithelium using genetically engineered mouse models (GEMMs).
- To evaluate the therapeutic potential of combining a PI3K inhibitor (BYL719) with cisplatin in PIK3CA-mutated oral squamous cell carcinoma (OSCC).
Main Methods:
- Development of GEMMs with tissue-specific expression of GOF PIK3CA (E20) allele, alone or with heterozygous p53 mutation.
- Induction of OSCC using 4-nitroquinoline 1-oxide and assessment of tumor progression, metastasis, and p16 loss.
- RNA-sequencing (RNA-seq) analysis of primary OSCC cell lines to identify differentially expressed genes.
- In vitro and in vivo evaluation of sensitivity to BYL719 and cisplatin combination therapy.
Main Results:
- GOF PIK3CA mutations promoted OSCC progression in GEMMs, with frequent distal metastasis observed in E20/p53 double mutants.
- Loss of p16 was associated with OSCC progression, mirroring findings in human OSCC.
- RNA-seq identified genes related to proliferation and cell cycle as commonly dysregulated.
- All tested OSCC cell lines, regardless of p53 or p16 status, showed enhanced sensitivity to the BYL719 and cisplatin combination therapy.
Conclusions:
- Oncogenic PIK3CA mutations contribute to OSCC progression and metastasis, particularly in the context of p53 loss.
- The combination of BYL719 and cisplatin demonstrates significant therapeutic potential for PIK3CA-mutated OSCC.
- This combination therapy warrants consideration for HNSCC patients with PIK3CA mutations, irrespective of p53 or p16 status.
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