All PI3K isoforms - α, β, γ and δ - are expressed in all the MCL cell lines tested...copanlisib is more potent in targeting MCL cells in vitro with IC50 at a nanomolar range. Copanlisib at low dosage of 6 mg/kg/2d significantly inhibited in vivo tumor growth of an ibrutinib-venetoclax dual-resistant PDX model...Volasertib at low dosage of 10 mg/kg/week diminished in vivo tumor growth of the ibrutinib-venetoclax dual-resistant PDX model. More interestingly, the combination of copanlisib and volasertib induced synergistic effects in ibrutinib-resistant, venetoclax-resistant, and ibrutinib-venetoclax dual-resistant cell lines in vitro. Moreover, combined treatment with copanlisib (6mg/kg/2d) and volasertib (5mg/kg/week) significantly enhanced anti-MCL activity in the same PDX model, compared to that of either single-agent treatment...