Bruton's Tyrosine Kinase Small Molecule Inhibitors Induce a Distinct Pancreatic Toxicity in Rats.
Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematologic cancers and autoimmune diseases. GDC-0853 ((S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one) is a selective and reversible oral small-molecule BTK inhibitor in development for the treatment of rheumatoid arthritis and systemic lupus erythematosus. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer caused pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation. Similar findings were not observed in mice or dogs at much higher exposures. Hemorrhage in the peri-islet vasculature emerged between four and seven daily doses of GDC-0853 and was histologically similar to spontaneously occurring changes in aging SD rats. This suggests that GDC-0853 could exacerbate a background finding in younger animals. Glucose homeostasis was dysregulated following a glucose challenge; however, this occurred only after 28 days of administration and was not directly associated with onset or severity of pancreatic lesions. There were no changes in other common serum biomarkers assessing endocrine and exocrine pancreatic function. Additionally, these lesions were not readily detectable via Doppler ultrasound, computed tomography, or magnetic resonance imaging. Our results indicate that pancreatic lesions in rats are likely a class effect of BTK inhibitors, which may exacerbate an islet-centered pathology that is unlikely to be relevant to humans.
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Rebecca I
RI
Erickson
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080 schutt.leah@gene.com.
Leah K
LK
Schutt
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Jacqueline M
JM
Tarrant
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Michelle
M
McDowell
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Lichuan
L
Liu
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Adam R
AR
Johnson
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Sock-Cheng
SC
Lewin-Koh
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Maj
M
Hedehus
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Jed
J
Ross
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Richard A D
RA
Carano
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Karin
K
Staflin
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Fiona
F
Zhong
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
James J
JJ
Crawford
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Shelly
S
Zhong
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Karin
K
Reif
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Arna
A
Katewa
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Harvey
H
Wong
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Wendy B
WB
Young
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Donna M
DM
Dambach
Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
Dinah L
DL
Misner
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000633:toxicity*; D011758:Pyrroles / Q000633:toxicity*; D051381:Rats; D013045:Species Specificity
D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011758:Pyrroles; C000619415:fenebrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D005947:Glucose