Rhabdomyosarcoma (RMS) is an aggressive muscle cancer and the most common soft tissue sarcoma of childhood. Insulin-like growth factor (IGF) signaling has a long precedent of relevance in ARMS. Despite the potential impact of Igf1r inhibition, we expect resistance to evolve in a subset of patients. In this study, we use the prototypic Igf 1r inhibitor, NVP-AEW541, to investigate the mechanism of resistance that evolve in vivo using a genetically engineered mouse model of ARMS. The results point to the potential therapeutic importance of simultaneous targeting of Igf1r and Her2 to abrogate resistance.

In the study we have shown that Igf1r and Her2 interact only in those mouse rhabdomyosarcoma tumor cells that are innately (rapidly) resistant to the Igf1r inhibitor, NVP-AEW541, but not in naïve, untreated cells. An increase in Her2 phosphorylation was observed on stimulation with IGF2 only in the resistant cells, whereas there was no change in the level of phosphorylated Her2 in untreated rhabdomyosarcoma cells stimulated with IGF2. Our study suggests that while Her2 may be of some biological importance for naïve rhabdomyosarcoma tumors, Her2 may become a critical Igf1r signaling pathway adjunct for the survival of tumor cells under selection pressure by an Igf1r inhibitor.

The results also suggest that the mechanism of Igf1r/Her2 crosstalk may be more complex than a simple receptor–receptor interaction. Since treatment with Lapatinib did not block the phosphorylation of Igf1r and instead caused an increase in phosphorylation of Igf1r, we speculate that yet-unidentified third party adapter molecules (possibly non-RTKs) with opposing actions may mediate Her2/Igf1r interactions in NVP-AEW541 resistant cells. Displaced from Her2 by a Her2 antagonist, these nonreceptor kinases would be free to interact with and stimulate Igf1r phosphorylation. Studies by colleagues have shown that c-Src physically interacts with Her2 in breast carcinoma cell lines and related studies have shown that Src can phosphorylate Igf1r. While additional studies are required to explore this possible mechanism of third party crosstalk, the observation of lapatinib-induced Igf1r phosphorylation highlights the potential importance of simultaneous targeting of Igf1r and Her2 as a therapeutic strategy.

In summary, we have shown that formation of Igf1r and Her2 heterodimers is one of the mechanisms of rapidly developing resistance to Igf1r inhibitors in rhabdomyosarcoma. The results have also shown that there is a functional crosstalk between these 2 receptors in that IGF ligand leads to Her2 phosphorylation and that a Her2 inhibitor improves sensitivity to an Igf1r inhibitor. This study has clinical significance because Igf1r inhibitors are currently being used in clinical trials and because resistance to Igf1r inhibitors can be reasonably expected in current and future clinical trials. The studies suggest that targeting both Igf1r and Her2 simultaneously may be a very promising approach in abrogating resistance to Igf1r inhibitors in rhabdomyosarcoma.

Reference:

Evasion Mechanisms to Igf1r Inhibition in Rhabdomyosarcoma
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