HNSCC, which includes malignant squamous lesions arising in the oral cavity, larynx and pharynx, is the seventh most common cancer in the world. HNSCC has a remarkable multiplicity and diversity of genetic alterations. Most genomic alterations in HNSCC converge in a handful of molecular pathways resulting in cell cycle deregulation, genomic instability, cell differentiation defects, and persistent mitogenic signaling, the latter involving aberrant PI3K/mTOR pathway activation thereby rendering HNSCC responsive to PI3K/mTOR inhibitors. Pathway is based on [Fig 1 from Iglesias-Bartolome et al](https://europepmc.org/articles/PMC4348071), [Fig 5 from Li et al](https://www.nature.com/articles/nature14129) and [Fig 33-3 from Clinicalgate](https://clinicalgate.com/the-molecular-pathogenesis-of-head-and-neck-cancer/). Description is modified from [Iglesias-Bartolome et al](https://europepmc.org/articles/PMC4348071). Protein phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org. ff8 fb2 f64 c82 RelA c-Rel parentid=P31751; parentsymbol=AKT2; site=sDGAtMKtFCGtPEy; position=thr309; sitegrpid=448537; ptm=p; direction=u parentid=P31749; parentsymbol=AKT1; site=kDGAtMKtFCGtPEy; position=thr308; sitegrpid=447856; ptm=p; direction=u parentid=P31749; parentsymbol=AKT1; site=RPHFPQFsysAsGtA; position=ser473; sitegrpid=447855; ptm=p; direction=u parentid=Q9Y243; parentsymbol=AKT3; site=tDAATMKtFCGtPEy; position=thr305; sitegrpid=448521; ptm=p; direction=u parentid=P49815; parentsymbol=TSC2; site=GLRPRGytISDsAPs; position=thr1462; sitegrpid=448546; ptm=p; direction=d parentid=P49815; parentsymbol=TSC2; site=sFRARstsLNERPKs; position=ser939; sitegrpid=448501; ptm=p; direction=d parentid=P42345; parentsymbol=MTOR; site=RsRtRtDsysAGQsV; position=ser2448; sitegrpid=447578; ptm=p; direction=u parentid=P42345; parentsymbol=MTOR; site=tVPEsIHsFIGDGLV; position=ser2481; sitegrpid=447498; ptm=p; direction=u parentid=P62753; parentsymbol=RPS6; site=IAKRRRLssLRAsts; position=ser235; sitegrpid=448092; ptm=p; direction=u parentid=P62753; parentsymbol=RPS6; site=AKRRRLssLRAstsK; position=ser236; sitegrpid=448093; ptm=p; direction=u parentid=Q13541; parentsymbol=EIF4EBP1; site=FLMECrNsPVtktPP; position=ser65; sitegrpid=447527; ptm=p; direction=d parentid=Q13541; parentsymbol=EIF4EBP1; site=rNsPVtktPPRDLPt; position=thr70; sitegrpid=447528; ptm=p; direction=d parentid=Q13541; parentsymbol=EIF4EBP1; site=GGtLFsttPGGtRII; position=thr46; sitegrpid=447496; ptm=p; direction=d parentid=Q13541; parentsymbol=EIF4EBP1; site=PPGDysttPGGtLFs; position=thr37; sitegrpid=447497; ptm=p; direction=d parentid=P42345; parentsymbol=MTOR; site=tVPEsIHsFIGDGLV; position=ser2481; sitegrpid=447498; ptm=p; direction=u parentid=P42345; parentsymbol=MTOR; site=RsRtRtDsysAGQsV; position=ser2448; sitegrpid=447578; ptm=p; direction=u HPV6 inactivates TP53 in tumors without somatic TP53 mutations f64 fb2 fb2 fb2 fb2 fb2 fb2 25514926 PubMed PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res 2015 Hornbeck PV Zhang B Murray B Kornhauser JM Latham V Skrzypek E PubMed https://clinicalgate.com/the-molecular-pathogenesis-of-head-and-neck-cancer/ cancer pathway PW:0000605 Pathway Ontology disease pathway PW:0000013 Pathway Ontology head and neck carcinoma DOID:1542 Disease 23847349 PubMed Exploiting the head and neck cancer oncogenome: widespread PI3K-mTOR pathway alterations and novel molecular targets. Cancer Discov 2013 Iglesias-Bartolome R Martin D Gutkind JS 31695792 PubMed Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment. Theranostics 2019 Li ZX Zheng ZQ Wei ZH Zhang LL Li F Lin L Liu RQ Huang XD Lv JW Chen FP He XJ Guan JL Kou J Ma J Zhou GQ Sun Y