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).

Acquired resistance develops when the Imbruvica-binding site on BTK contains the C481S mutation, which blocks inhibition of BTK and allows downstream signaling.

[b] BTK 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 activation.

[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.

[d] Prolonging G1 also activates the phosphoinositide 3-kinase (PI3K) negative 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.