FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice

Abstract

Breast cancers commonly become resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs); however, the mechanisms of this resistance remain largely unknown. We hypothesized that resistance may originate, at least in part, from molecular alterations that activate signaling downstream of EGFR. Using a screen to measure reversion of malignant cells into phenotypically nonmalignant cells in 3D gels, we identified FAM83A as a candidate cancer-associated gene capable of conferring resistance to EGFR-TKIs. FAM83A overexpression in cancer cells increased proliferation and invasion and imparted EGFR-TKI resistance both in cultured cells and in animals. Tumor cells that survived EGFR-TKI treatment in vivo had upregulated FAM83A levels. Additionally, FAM83A overexpression dramatically increased the number and size of transformed foci in cultured cells and anchorage-independent growth in soft agar. Conversely, FAM83A depletion in cancer cells caused reversion of the malignant phenotype, delayed tumor growth in mice, and rendered cells more sensitive to EGFR-TKI. Analyses of published clinical data revealed a correlation between high FAM83A expression and breast cancer patients' poor prognosis. We found that FAM83A interacted with and caused phosphorylation of c-RAF and PI3K p85, upstream of MAPK and downstream of EGFR. These data provide an additional mechanism by which tumor cells can become EGFR-TKI resistant.

FAM83B mediates EGFR- and RAS-driven oncogenic transformation

“…In fact, Lee et al demonstrated that FAM83A can activate both MAPK and PI3K-AKT signaling (9). Upon analysis of GFP-and FAM83B-expressing cells stimulated with EGF, we also noted prolonged AKT and EGFR phosphorylation, similar to our observation of MAPK signaling (Supplemental Figure 13).…”

“…Interestingly, Lee et al have identified another FAM83 member, FAM83A, based on its ability to confer resistance to EGFR-TKIs in a forward genetics cDNA library screen (9). Similar to their findings, we found that FAM83B-expressing cells had sustained ERK1/2 phosphorylation and enhanced proliferation in the presence of EGFR-TKIs (AG1478, erlotinib, and CL387785) compared with control cells (Figure 6, C and D, and Supplemental Figure 8).…”

“…Taken together, our data suggest that tumors has been identified as a lung cancer biomarker, reported to be elevated in approximately 70% of lung adenocarcinomas (17). In addition, FAM83A is overexpressed in breast cancer, is associated with poor prognosis, activates MAPK and PI3K-AKT signaling, and confers decreased sensitivity to EGFR-TKIs (9). Analysis of publically available microarray data revealed that many of the FAM83 members were also overexpressed in cancer.…”

FAM83A and FAM83B: candidate oncogenes and TKI resistance mediators

“…Several of these themes are highlighted by articles appearing in the current issue of the JCI, in which two groups, using related approaches, focused on members of the family with sequence similarity, members A and B (FAM83A and FAM83B) (7,8). Although differences between these reports clearly exist, the findings and conclusions of these groups exhibit marked similarities and suggest that these genes may contribute both to the pathophysiology of breast cancer as well as to resistance to EGFR inhibitors.…”

Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice

“…Therefore, the blockade of EGFR has been validated as an effective approach for cancer therapy. Unfortunately, EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy has been impeded by resistance [8,9] . Thus, it is important to explore effective means of characterizing patterns of resistance over time and to optimize treatment to prevent or at least prolong the time to EGFR-TKI resistance.…”