Thursday, August 28, 2014
Cover Story: Overcoming ibrutinib resistance
Figure 1. Blocking
signaling to overcome Imbruvica resistance in MCL cells. [a] B
cell receptor (BCR) stimulation by an extracellular antigen induces Bruton's tyrosine kinase
(BTK) activation in
mantle cell lymphoma (MCL) cells. Activation is higher in MCL cells than normal
B cells. BTK inhibitors such as Imbruvica ibrutinib
act by directly binding BTK to block downstream signaling. In addition,
Imbruvica indirectly inhibits protein kinase B (PKB; PKBA; AKT; AKT1).
develops when the Imbruvica-binding site on BTK contains the C481S mutation,
which blocks inhibition of BTK and allows downstream signaling.
signaling ultimately leads to NF-kB activation through a
pathway that involves phospholipase Cg2 (phosphatidylinositol-specific)
(PLCG2) and protein kinase Cb (PRKCB), which promotes
cell proliferation and survival. Inhibiting BTK blocks this source of NF-kB
[c] In a
separate pathway, inhibition of cyclin dependent kinase 4
(CDK4) stalls and
prolongs the MCL cell cycle in the G1 phase. Prolonging G1 also inhibits NF-kB
activation. Therefore, halting the cell cycle at G1 with CDK4 and CDK6 inhibitors can
help block cell proliferation caused by ibrutinib resistance.
Prolonging G1 also activates the phosphoinositide 3-kinase
regulator phosphoinositide 3-kinase interacting
protein 1 (PIK3IP1; HGFL) to inhibit
activation of the PI3K pathway.
[e] PI3K also
activates AKT in MCL cells and leads to cell proliferation and survival through
mammalian target of rapamycin
(mTOR; FRAP; RAFT1) activation.
Imbruvica indirectly inhibits AKT and blocks signaling through this pathway. In
addition, PI3K inhibitors prevent downstream activation of AKT and block
another prosurvival pathway. MCL cells with primary resistance to Imbruvica
proliferate despite inhibition of BTK by the drug. Resistance may be caused by
persistent activation of the PI3K-AKT pathway. The CDK4 and CDK6 inhibitor
palbociclib can restore Imbruvica sensitivity in cell models of acquired
resistance. Combinations of palbociclib with different PI3K inhibitors can
overcome Imbruvica resistance in cell models of acquired or primary resistance.