Abstract
BTK and PI3K inhibitors are among the drugs approved for the treatment of patients with lymphoid neoplasms. Although active, their ability to lead as single agents to long-lasting complete remission is rather limited especially in the lymphoma setting. This indicates that tumor cells often develop resistance to the drugs. Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors and that targeted pharmacological interventions can restore sensitivity to the small molecules.
We started from a marginal zone lymphoma (MZL) cell line, Karpas-1718, kept under prolonged exposure to the PI3Kδ inhibitor idelalisib until acquisition of resistance, or with no drug. Cells underwent transcriptome, miRNA and methylation profiling, whole exome sequencing, and pharmacological screening which led to the identification of the overexpression of ERBB4 and its ligands HBEGF and NRG2 in the resistant cells. Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting. Addition of recombinant HBEGF induced resistance to BTK and PI3K inhibitors in parental cells but also in additional lymphoma models. Combination with the ERBB inhibitor lapatinib was beneficial in resistant cells and in other lymphoma models already expressing the identified resistance factors. Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors, and pretreatment with demethylating agents or EZH2 inhibitors overcame the resistance. Resistance factors were shown to be expressed in clinical samples, further extending the findings of the study.
In conclusions, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors and treatments that appear to overcome it.
Key points
A mechanism of secondary resistance to the PI3Kδ and BTK inhibitors in B cell neoplasms driven by secreted factors.
Resistance can be reverted by targeting ERBB signaling.
Competing Interest Statement
Alberto J. Arribas: travel grant from Astra Zeneca. Luciano Cascione: travel grant from HTG. Chiara Tarantelli: travel grant from iOnctura. Anastasios Stathis: institutional research funds from: Bayer, ImmunoGen, Merck, Pfizer, Novartis, Roche, MEI Pharma, ADC-Therapeutics; travel grant from AbbVie and PharmaMar. Valter Gattei: research funding from Menarini SpA, laboratory activities fees from Janssen, scientific advisory board fees from AbbVie. Georg Stussi: travel grants from Novartis, Celgene, Roche; consultancy fee from Novartis; scientific advisory board fees from Bayer, Celgene, Janssen, Novartis; speaker fees from Gilead. Jennifer Brown: consultant for Abbvie, Acerta, Astra-Zeneca, Beigene, Catapult, Dynamo Therapeutics, Eli Lilly, Genentech/Roche, Gilead, Juno/Celgene/Bristol Myers Squibb, Kite, Loxo, MEI Pharma, Nextcea, Novartis, Octapharma, Pfizer, Pharmacyclics, Rigel, Sunesis, TG Therapeutics, Verastem; research funding from Gilead, Loxo, Sun, TG Therapeutics and Verastem; served on data safety monitoring committees for Invectys. Emanuele Zucca: institutional research funds from Celgene, Roche and Janssen; advisory board fees from Celgene, Roche, Mei Pharma, Astra Zeneca and Celltrion Healthcare; travel grants from Abbvie and Gilead; expert statements provided to Gilead, Bristol-Myers Squibb and MSD. Davide Rossi: grant support from Gilead, AbbVie, Janssen; honoraria from Gilead, AbbVie Janssen, Roche; scientific advisory board fees from Gilead, AbbVie, Janssen, AstraZeneca, MSD. Francesco Bertoni: institutional research funds from Acerta, ADC Therapeutics, Bayer AG, Cellestia, CTI Life Sciences, EMD Serono, Helsinn, HTG Molecular Diagnostics, ImmunoGen, iOnctura, Menarini Ricerche, NEOMED Therapeutics 1, Nordic Nanovector ASA, Oncology Therapeutic Development, PIQUR Therapeutics AG; consultancy fee from Helsinn, Menarini; expert statements provided to HTG Molecular Diagnostics; travel grants from Amgen, Astra Zeneca, Jazz Pharmaceuticals, PIQUR Therapeutics AG. The other Authors have nothing to disclose.