Reference Detail

Ref Type

Journal Article

PMID

(30108165)

Authors

Nisa L, Barras D, Medová M, Aebersold DM, Medo M, Poliaková M, Koch J, Bojaxhiu B, Eliçin O, Dettmer MS, Angelino P, Giger R, Borner U, Caversaccio MD, Carey TE, Ho L, McKee TA, Delorenzi M, Zimmer Y

Title

Comprehensive Genomic Profiling of Patient-matched Head and Neck Cancer Cells: A Preclinical Pipeline for Metastatic and Recurrent Disease.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer research : MCR	16	12	2018 12	1912-1926	Mol Cancer Res

URL

Abstract Text

Metastases and tumor recurrence have a major prognostic impact in head and neck squamous cell carcinoma (HNSCC); however, cellular models that comprehensively characterize metastatic and recurrent HNSCC are lacking. To this end, we obtained genomic, transcriptomic, and copy number profiles of the UM-SCC cell line panel, encompassing patient-matched metastatic and recurrent cells. UM-SCC cells recapitulate the most prevalent genomic alterations described in HNSCC, featuring common TP53, PI3K, NOTCH, and Hippo pathway mutations. This analysis identified a novel F977Y kinase domain PIK3CA mutation exclusively present in a recurrent cell line (UM-SCC14B), potentially conferring resistance to PI3K inhibitors. Small proline-rich protein 2A (SPRR2A), a protein involved in epithelial homeostasis and invasion, was one of the most consistently downregulated transcripts in metastatic and recurrent UM-SCC cells. Assessment of SPRR2A protein expression in a clinical cohort of patients with HNSCC confirmed common SPRR2A downregulation in primary tumors (61.9% of cases) and lymph node metastases (31.3%), but not in normal tissue. High expression of SPRR2A in lymph node metastases was, along with nonoropharyngeal location of the primary tumor, an independent prognostic factor for regional disease recurrence after surgery and radiotherapy (HR 2.81; 95% CI, 1.16-6.79; P = 0.02). These results suggest that SPRR2A plays a dual role in invasion and therapeutic resistance in HNSCC, respectively through its downregulation and overexpression. IMPLICATIONS: The current study reveals translationally relevant mechanisms underlying metastasis and recurrence in HNSCC and represents an adjuvant tool for preclinical research in this disease setting. Underlining its discovery potential this approach identified a PIK3CA-resistant mutation as well as SPRR2A as possible theragnostic markers.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
PIK3CA	F977Y	missense	unknown	PIK3CA F977Y lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). F977Y has been associated with resistance to a PI3K inhibitor in culture (PMID: 30108165), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Mar 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA F977Y	head and neck squamous cell carcinoma	resistant	Pictilisib	Preclinical - Cell culture	Actionable	In a preclinical study, a head and neck squamous cell carcinoma cell line harboring PIK3CA F977Y demonstrated resistance to growth inhibition by Pictilisib (GDC-0941) in culture (PMID: 30108165).	30108165