FAM83A and FAM83B are oncogenic and confer resistance to EGFR-TKIs.
Major finding: FAM83A and FAM83B are oncogenic and confer resistance to EGFR-TKIs.
Mechanism: FAM83 proteins enhance MAPK signaling by increasing c-RAF membrane localization and activation.
Impact: FAM83 inhibition may selectively target cancer cells and improve the efficacy of TKI therapy.
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) are commonly used to treat breast and lung tumors with EGFR overexpression. However, drug resistance has limited the efficacy of these therapies, emphasizing the importance of understanding compensatory downstream signals. Using a screen for phenotypic reversion of malignant cells, Lee and colleagues identified family with sequence similarity 83, member A (FAM83A) as a candidate oncogene that conferred EGFR-TKI resistance and promoted the depolarization and proliferation of breast cancer cells in 3-dimensional cultures. Overexpression of FAM83A enhanced anchorage-independent growth, cell invasion, and lapatinib resistance in vivo. In contrast, depletion of FAM83A significantly inhibited xenograft tumor growth and increased the sensitivity of FAM83A-expressing breast cancer cells to EGFR inhibitors. Cipriano and colleagues reported complementary findings for the related FAM83B, which was isolated via an independent insertional mutagenesis screen as a gene that could substitute for RAS to facilitate oncogenic transformation via its N-terminal domain of unknown function (DUF1669). Similar to FAM83A, FAM83B induced anchorage-independent growth and decreased EGFR inhibitor sensitivity, whereas loss of FAM83B expression suppressed tumorigenesis, suggesting that cancer cells are dependent on FAM83 proteins for malignant transformation. These oncogenic effects were dependent on FAM83 binding to c-RAF downstream of EGFR and RAS; Cipriano and colleagues showed that this interaction prevented 14-3-3–mediated cytoplasmic sequestration of c-RAF, and both groups demonstrated that FAM83 proteins enabled EGFR-independent activation of MAPK and PI3K/AKT signaling. Interestingly, both studies also showed that FAM83 expression was elevated in human breast and lung cancer samples and that high FAM83 levels were correlated with poor prognosis, suggesting that these proteins may drive tumor progression. Together, these results provide evidence of an oncogenic function for these proteins and support the development of FAM83-specific inhibitors to overcome EGFR-TKI resistance in cancer therapy.
Lee SY, Meier R, Furuta S, Lenburg ME, Kenny PA, Xu R, et al. FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice. J Clin Invest 2012 Aug 13 [Epub ahead of print].