SLC3A2-NRG1 fusion

Taken together, this is the first study to report that KRAS mutation increased NRG1 cleavage from the S-N fusion protein through ADAM17, thereby enhancing the Ras/Raf/MEK/ERK and ERBB/PI3K/Akt/mTOR pathways. Moreover, the coexistence of KRAS mutant and S-N fusion in lung tumours renders them vulnerable to MEK1/2 and/or ADAM17 inhibitors, at least in part, due to their dependency on the strong positive loop between KRAS mutation and S-N fusion.

Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of NRG1 fusion-dependent tumorigenesis in vitro and in vivo in breast, lung and ovarian patient-derived cancer models.

There was no shrinkage of afatinib-treated pancreatic PDX tumors.Our results here suggest that seribantumab is effective at reducing tumor growth in preclinical models of gastrointestinal cancers with NRG1 fusions. These data support the use of seribantumab to treat GI and other cancers with NRG1 fusions in the ongoing phase 2 CRESTONE study (NCT#04383210).

Finally, we assessed the ability of Zeno to induce antibody-dependent cellular cytotoxicity using a chromium release assay and peripheral blood mononuclear cells. Zeno induced significant cytotoxicity in MDA-MB-175-VII cells while a non-ADCC enhanced, non-specific IgG had no effect.Here we show that Zeno effectively blocks the growth of NRG1 fusion-positive cell line and xenograft models of tumors arising from lung, pancreas and other organs, and these results support the continued development of Zeno to treat patients with this molecularly defined subset of cancers.