Enhanced Sensitivity of Idelalisib and Ibrutinib-Resistant Cell Lines to Anti-CD38 Antibodies

Author(s): Matera Eva-Laure, Fouret Julien, Baulu Estelle, Perrial Emeline, Bousfiha Zineb, Abdelkamel Chettab, Lars Petter Jordheim, Charles Dumontet

BCR pathway inhibitors idelalisib and ibrutinib were the first small molecule targeted agents for B-cell malignancies. In spite of encouraging response rates in various forms of B cell diseases, patients will eventually develop relapse due to the emergence of resistant cells. To better identify the possible mechanisms of resistance we developed and characterized idelalisib- and ibrutinib-resistant variants of the human non Hodgkin’s lymphoma cell lines DoHH2 and Daudi. These resistant variants displayed a cross-resistance profile limited to PI3K inhibitors, BTK inhibitors and a SYK inhibitor but not to unrelated agents. A number of alterations were observed in the resistant lines, including a strong reduction of BLINK and the AKT3. A new SNP in PLCgamma2 (Leu848Phe) closely related to a previously reported SNP associated to ibrutinib resistance (Leu845Phe) was observed in both DAUDI-based resistant cell lines but was absent in wild type cells. Resistant lines tended to express larger amounts of CD38 and were found to display enhanced sensitivity to anti-CD38 antibodies. These results identify potential novel mechanisms of resistance to idelalisib and ibrutinib and raise the possibility that cells resistant to BCR pathway inhibitors might possess enhanced sensitivity to anti-CD38 antibodies.