Frederick Wilson, MD, Ph.D., Instructor in Medicine, Harvard Medical School

Boston, MA

Current Site Of Practice: Boston
Hospital Affiliation: Dana-Farber
Focus of Research: Cancer genomics
Fellowship Year: 2015 – 2016
Attended: Harvard

Contact Frederick Wilson


MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells

Co-Authors Kryukov GV, Wilson FH, Ruth JR, Paulk J, Tsherniak A, Marlow SE, Vazquez F, Weir BA, Fitzgerald ME, Tanaka M, Bielski CM, Scott JM, Dennis C, Cowley GS, Boehm JS, Root DE, Golub TR, Clish CB, Bradner JE, Hahn WC, Garraway LA

The discovery of cancer dependencies has the potential to inform therapeutic strategies
and to identify putative drug targets. Integrating data from comprehensive genomic
profiling of cancer cell lines and from functional characterization of cancer cell
dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase
(MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5)
and its binding partner WDR77. MTAP is frequently lost due to its proximity to the
commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular
concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells
harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic
activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a
modest preferential impairment of cell viability for MTAP-null cancer cell lines compared
with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a
potential vulnerability across multiple cancer lineages augmented by a common
“passenger” genomic alteration.

Science 2016 Mar 11; 351 (6278): 1214-18


A functional landscape of resistance to ALK inhibition in lung cancer

Co-Authors Wilson FH, Johannessen CM, Piccioni F, Tamayo P, Kim JW, Van Allen EM, Corsello SM, Capelletti M, Calles A, Butaney M, Sharifnia T, Gabriel SB, Mesirov JP, Hahn WC, Engelman JA, Meyerson M, Root DE, Jänne PA, Garraway LA

We conducted a large-scale functional genetic study to characterize mechanisms of resistance to ALK inhibition in ALK-dependent lung cancer cells. We identify members of known resistance pathways and additional putative resistance drivers. Among the latter were members of the P2Y purinergic receptor family of G-protein-coupled receptors (P2Y1, P2Y2, and P2Y6). P2Y receptors mediated resistance in part through a protein-kinase-C (PKC)-dependent mechanism. Moreover, PKC activation alone was sufficient to confer resistance to ALK inhibitors, whereas combined ALK and PKC inhibition restored sensitivity. We observed enrichment of gene signatures associated with several resistance drivers (including P2Y receptors) in crizotinib-resistant ALK-rearranged lung tumors compared to treatment-naive controls, supporting a role for these identified mechanisms in clinical ALK inhibitor resistance.

Cancer Cell. 2015 Mar 9;27(3):397-408