The present invention relates to HPV-positive as well as HPV-negative screening platforms that are highly serum-dependent, for use as HNSCC models. These HNSCC models die reproducibly in serum-deprived conditions and the introduction of driver mutations (or increased levels of the WT gene) confers enhanced cell survival and proliferation under serum deprivation. These platforms have the major advantages of allowing functional screening of mutations in relevant HNSCC models (HPV-positive and HPV-negative). In addition to oncogene screening, this model can also be used in drug discovery. Specifically, cells expressing mutations that confer increased survival can then be screened against panels of therapeutic agents to determine if the mutation(s) can predict the optimal treatment for patients whose tumors harbor the mutation(s).