Functional evaluation of genetic lesions can discover a role in cancer initiation and progression and help develop novel therapeutic strategies. We previously identified the negative MAPK regulator SPRED1 as a novel tumor suppressor in KIT-driven melanoma. Here, we show that SPRED1 is also frequently deleted in human melanoma driven by mutant BRAF. We found that SPRED1 inactivation in human melanoma cell lines and primary zebrafish melanoma conferred resistance to BRAFV600E inhibition in vitro and in vivo. Mechanistically, SPRED1 loss promoted melanoma cell proliferation under mutant BRAF inhibition by reactivating MAPK activity. Consistently, biallelic deletion of SPRED1 was observed in a patient whose melanoma acquired resistance to MAPK-targeted therapy. These studies combining work in human cells and in vivo modeling in zebrafish demonstrate a new mechanism of resistance to BRAFV600E inhibition in melanoma.
SPRED1 deletion confers resistance to MAPK inhibition in melanoma
Disclosures: R.S. Lo reported grants from Pfizer, Merck, OncoSec, and BMS outside the submitted work. L.I. Zon reported personal fees from Scholar Rock Inc., Fate Therapeutics, CAMP4 Therapeutics, Amagma Therapeutics, Celularity, and Cellarity outside the submitted work. No other disclosures were reported.
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Julien Ablain, Sixue Liu, Gatien Moriceau, Roger S. Lo, Leonard I. Zon; SPRED1 deletion confers resistance to MAPK inhibition in melanoma. J Exp Med 1 March 2021; 218 (3): e20201097. doi: https://doi.org/10.1084/jem.20201097
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