Significance The development of novel, effective treatments for patients with advanced/recurrent cervical cancer remains an unmet medical need. Using whole-exome sequencing, we identified multiple genes with recurrent alterations in cervical cancer, including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle pathways. Using fully sequenced cell lines and xenografts, we found pan-HER (afatinib/neratinib) and PIK3CA (copanlisib) inhibitors to be active, but only transiently effective in controlling the in vivo growth of PIK3CA-mutated cervical tumor xenografts. In contrast, the combination of irreversible pan-HER kinase and PIK3CA inhibitors was highly synergistic and able to induce durable regression of xenografts harboring derangements in the ERBB2/PI3K/AKT/mTOR pathway in vivo. These findings suggest a large subset of cervical tumors (>70%) might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.