Abstract: Described herein is the finding that the PI3K/Akt and TGF-? pathways act cooperatively to promote squamous cell carcinoma (SCC), such as head and neck squamous cell carcinoma (HNSCC). In particular, it was found that conditional deletion of transforming growth factor-? receptor type I (TGFBR1) and phosphatase and tensin homolog (PTEN) in head and neck epithelia of mice led to spontaneous development of SCC in the mice with complete penetrance. Accordingly, provided herein are methods of treating a subject diagnosed with SCC by administering to the subject a therapeutically effective amount of an inhibitor of the PI3K/Akt pathway and a therapeutically effective amount of a modulator of the TGF-? pathway. Also provided is a method of diagnosing a subject as having SCC, or being susceptible to developing SCC, by detecting the presence or absence of at least one tumor-associated mutation in the TGFBR1 gene and at least one tumor-associated mutation in the PTEN gene.