Frequent co-expression of EGFR and NeuGcGM3 ganglioside in cancer: it’s potential therapeutic implications

Abstract

Interaction between epidermal growth factor receptor (EGFR) signaling with GM3 ganglioside expression has been previously described. However, little is known about EGFR and NeuGcGM3 co-expression in cancer patients and their therapeutic implications. In this paper, we evaluate the co-expression of EGFR and NeuGcGM3 ganglioside in tumors from 92 patients and in two spontaneous lung metastasis models of mice (Lewis lung carcinoma (3LL-D122) in C57BL/6 and mammary carcinoma (4T1) in BALB/c). As results, co-expression of EGFR and NeuGcGM3 ganglioside was frequently observed in 63 of 92 patients (68 %), independently of histological subtype. Moreover, EGFR is co-expressed with NeuGcGM3 ganglioside in the metastasis of 3LL-D122 and 4T1 murine models. Such dual expression appears to be therapeutically relevant, since combined therapy with mAbs against these two molecules synergistically increase the survival of mice treated. Overall, our results suggest that NeuGcGM3 and EGFR may coordinately contribute to the tumor cell biology and that therapeutic combinations against these two targets might be a valid strategy to explore.

Synergistic potentiation of the anti-metastatic effect of anti EGFR mAb by its combination with immunotherapies targeting the ganglioside NGcGM3

“…EGFR and NGcGM3 ganglioside are molecules co-expressed on spontaneous lung metastases induced by 3LL-D122 or 4T1-clones [ 28 ]. Interestingly in the 3LL-model, NGcGM3 expression increases progressively from the primary tumor to the lung metastasis [ 29 ], being almost inexistent on the tumor cells when cultured in vitro .…”

“…Additionally, we substituted the ganglioside vaccine for a passive therapy with the 14F7 mAb, which is specific for NGcGM3 ganglioside [ 32 ]. Previously, we reported that the combination therapy using the mAbs 7A7 and 14F7 increases the overall survival on the models of experimental lung metastasis of 3LL-D122 [ 28 ]. Here we further evaluated this combination of passive therapies, but in the spontaneous lung metastasis model (3LL-D122-cells) [ 28 ].…”

“…Previously, we reported that the combination therapy using the mAbs 7A7 and 14F7 increases the overall survival on the models of experimental lung metastasis of 3LL-D122 [ 28 ]. Here we further evaluated this combination of passive therapies, but in the spontaneous lung metastasis model (3LL-D122-cells) [ 28 ]. We found that 30% of the mice consistently remain alive only the combination group.…”

“…A recent in vitro study demonstrated that EGFR phosphorylation in A431 cell lines is less inhibited in the presence of NGcGM3 than in the presence of NAcGM3 [ 24 ]. Moreover, co-expression of NGcGM3 and EGFR is a relatively frequent phenomena in cancer patients [ 28 ] and what it is more relevant the over-expression of both EGFR and NGcGM3 variant correlates with a worst prognostic in NSCLC patients [ 21 ] than the overexpression of either of these molecules separately.…”

Biological Roles of Aberrantly Expressed Glycosphingolipids and Related Enzymes in Human Cancer Development and Progression

“…NeuGcGM3, because of its selective expression in tumors, is a potentially useful target for immunotherapy, e.g., using Racotumomab-alum vaccine ( Alfonso et al, 2014 ) or recombinant monoclonal antibody 14F7 ( Piperno et al, 2015 ). In cases in which NeuGcGM3 and EGFR are involved jointly in tumor cell metastasis, therapeutic strategies that simultaneously target both molecules may be effective ( Palomo et al, 2016 ).…”