Abstract 842P
Background
PI3Kδ has a central role in the BCR signaling in hematological malignancies. Idelalisib was the first-in-class PI3Kδ inhibitor, and several novel compounds are undergoing clinical investigation. To identify modalities to overcome the resistance developed to these agents, we have developed idelalisib-resistant models derived from MZL cell lines.
Methods
Cells were kept under idelalisib until acquisition of resistance or with no drug (parental). Stable resistance was confirmed by MTT assay. Cells underwent transcriptome, miRNA (RNA-Seq) and methylation profiling, whole exome sequencing, pharmacological screening, immunoblotting and immunophenotyping. Cytokines secretion was evaluated by ELISA in cell lines and patients serum samples.
Results
Two resistant cell lines were obtained from VL51 and Karpas1718 with IC50s 20-30 fold times higher than parental. In both models, conditioned media from resistant transferred the resistance to the parental cells. Karpas1718 model exhibited elevated pAKT, pERK, B cell proliferation, ERBB signaling and HBEGF secretion. Addition of recombinant HBEGF induced resistance to idelalisib and to ibrutinib in the parental cells and in mantle cell lymphoma models. Combination with the ERBB inhibitor lapatinib recovered sensitivity to idelalisib. VL51 model showed enrichment in IL6/STAT and PDGFR signatures, and pERK and pSTAT. Multi-omics analysis underlined epigenetic reprogramming affecting expression of resistance-related factors. Resistant cells had higher PDGFRA surface expression and IL6 secretion. Pharmacological or genetic inhibition of IL6 or PDGFRA recovered sensitivity to idelalisib. Finally, IL6, PDGFRA and HBEGF expression levels were negatively correlated with idelalisib sensitivity in a panel of B-cell lymphoma models and serum of non-responders to idelalisib exhibited significantly higher levels of IL6 and HBEGF compared to clinically matched responders.
Conclusions
We identified two mechanisms of resistance to the PI3Kd inhibitor idelalisib driven by secreted factors, which were validated in clinical specimens and that have already allowed the identification treatments that might overcome resistance.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Institute of Oncology Research.
Funding
Swiss National Science Foundation (SNSF).
Disclosure
A.A. Mensah: Financial Interests, Institutional, Other, travel grant: Helsinn. A. Stathis: Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: ImmunoGen; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: MEI Pharma; Financial Interests, Institutional, Research Grant: ADC Therapeutics; Financial Interests, Institutional, Other, travel grant: PharmaMar; Financial Interests, Institutional, Other, travel grant: AbbVie. G. Stussi: Financial Interests, Institutional, Advisory Role: Novartis; Financial Interests, Institutional, Other, travel grants: Novartis; Financial Interests, Institutional, Other, travel grants: Celgene; Financial Interests, Institutional, Other, travel grants: Roche; Financial Interests, Institutional, Advisory Board: Bayer; Financial Interests, Institutional, Advisory Board: Celgene; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Invited Speaker: Gilead. V. Gattei: Financial Interests, Institutional, Research Grant: Menarini; Financial Interests, Institutional, Other, laboratory activities fees: Janssen; Financial Interests, Institutional, Advisory Board: AbbVie. J.R. Brown: Financial Interests, Institutional, Advisory Role: AbbVie; Financial Interests, Institutional, Advisory Role: Acerta; Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Institutional, Advisory Role: Beigene; Financial Interests, Institutional, Advisory Role: Catapult; Financial Interests, Institutional, Advisory Role: Dynamo Therapeutics; Financial Interests, Institutional, Advisory Role: Eli Lilly; Financial Interests, Institutional, Advisory Role: Genentech/Roche; Financial Interests, Institutional, Advisory Role: Gilead; Financial Interests, Institutional, Advisory Role: Juno/Celgene/Bristol Myers Squibb; Financial Interests, Institutional, Advisory Role: Kite; Financial Interests, Institutional, Advisory Role: Loxo; Financial Interests, Institutional, Advisory Role: MEI Pharma; Financial Interests, Institutional, Advisory Role: Nextcea; Financial Interests, Institutional, Advisory Role: Novartis; Financial Interests, Institutional, Advisory Role: Octapharma; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Advisory Role: Pharmacyclics; Financial Interests, Institutional, Advisory Role: Rigel; Financial Interests, Institutional, Advisory Role: Sunesis; Financial Interests, Institutional, Advisory Role: TG Therapeutics; Financial Interests, Institutional, Advisory Role: Verastem; Financial Interests, Institutional, Research Grant: Gilead; Financial Interests, Institutional, Research Grant: Loxo; Financial Interests, Institutional, Research Grant: Sun; Financial Interests, Institutional, Research Grant: TG Therapeutics; Financial Interests, Institutional, Research Grant: Verastem; Financial Interests, Institutional, Other, served on data safety monitoring committees: Invectys. E. Zucca: Financial Interests, Institutional, Research Grant: Celgene; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Advisory Board: Celgene; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Advisory Board: Mei Pharma; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Celltrion Healthcare; Financial Interests, Institutional, Other, travel grant: AbbVie; Financial Interests, Institutional, Other, travel grant: Gilead; Financial Interests, Institutional, Expert Testimony: Gilead; Financial Interests, Institutional, Expert Testimony: Bristol Myers Squibb; Financial Interests, Institutional, Expert Testimony: MSD. D. Rossi: Financial Interests, Institutional, Research Grant: Gilead; Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Other, honoraria: Gilead; Financial Interests, Institutional, Other, honoraria: AbbVie; Financial Interests, Institutional, Other, honoraria: Janssen; Financial Interests, Institutional, Other, honoraria: Roche; Financial Interests, Institutional, Advisory Board: Gilead; Financial Interests, Institutional, Advisory Board: AbbVie; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: MSD. F. Bertoni: Financial Interests, Institutional, Research Grant: Acerta; Financial Interests, Institutional, Research Grant: ADC Therapeutics; Financial Interests, Institutional, Research Grant: Bayer AG; Financial Interests, Institutional, Research Grant: Cellestia; Financial Interests, Institutional, Research Grant: CTI Life Sciences; Financial Interests, Institutional, Research Grant: ImmunoGen; Financial Interests, Institutional, Research Grant: Menarini Ricerche; Financial Interests, Institutional, Research Grant: NEOMED Therapeutics 1; Financial Interests, Institutional, Research Grant: Nordic Nanovector ASA; Financial Interests, Institutional, Research Grant: PIQUR Therapeutics AG; Financial Interests, Institutional, Research Grant: Helsinn; Financial Interests, Institutional, Advisory Role: Helsinn; Financial Interests, Institutional, Advisory Role: Menarini; Financial Interests, Institutional, Other, travel grant: Amgen; Financial Interests, Institutional, Other, travel grant: AstraZeneca; Financial Interests, Institutional, Other, travel grant: Jazz Pharmaceuticals. All other authors have declared no conflicts of interest.