BET protein bromodomain inhibitor-based combinations are highly active against post-myeloproliferative neoplasm secondary AML cells

Abstract

Myeloproliferative Neoplasms with myelofibrosis (MPN-MF) demonstrate constitutive activation of JAK-STAT signaling, which responds to treatment with the JAK1 & 2 kinase inhibitor (JAKi) ruxolitinib. However, MPN-MF often progresses (~20%) to secondary AML (sAML), where standard induction chemotherapy or ruxolitinib is relatively ineffective, necessitating the development of novel therapeutic approaches. In the present studies, we demonstrate that treatment with BET (bromodomain and extra terminal) protein inhibitor (BETi), e.g., JQ1, inhibits growth and induces apoptosis of cultured and primary, patient-derived (PD), post-MPN sAML blast progenitor cells. Reverse-phase protein array, mass-cytometry and Western analyses revealed that BETi treatment attenuated the protein expressions of c-MYC, p-STAT5, Bcl-xL, CDK4/6, PIM1 and IL-7R, while concomitantly inducing the levels of HEXIM1, p21 and BIM in the sAML cells. Co-treatment with BETi and ruxolitinib synergistically induced apoptosis of cultured and PD sAML cells, as well as significantly improved survival of immune-depleted mice engrafted with human sAML cells. While BETi or heat shock protein (HSP) 90 inhibitor alone exerted lethal activity, co-treatment with BETi and HSP90i was synergistically lethal against the ruxolitinib-persister or ruxolitinib-resistant sAML cells. Collectively, these findings further support in vivo testing of BETi-based combinations with JAKi and HSP90i against post-MPN sAML cells.

The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies

“…In plasmacytomas arising from Gp130 activation alone, activating genetic alterations in the c-MYC locus were recovered in three of ten independently arising tumors (33). Combining JAK and BET inhibitors is a potentially promising strategy for other hematologic malignancies, including JAK2V617-dependent myeloproliferative neoplasms and acute lymphocytic leukemia (ALL) characterized by IL7R activation (35)(36)(37)(38). In the ALL models, JQ-1 suppressed STAT5dependent signaling and improved survival; significantly at relapse, these tumors showed reactivation of STAT5 signaling indicating a feedback upregulation of JAK-STAT signaling.…”

Epigenetic treatment combinations to effectively target cisplatin‐resistant germ cell tumors: past, present, and future considerations

“…They are the only domains, which bind specifically to histone acetylation marks (Jain & Barton, 2017). Recently, the anti-cancer efficacy of inhibitors against the bromodomain and extra-terminal domain-containing (BET) protein family have been evaluated in several cancers, such as prostate, breast, colon, intestine, pancreas, liver, lung, brain, oral squamous cell carcinoma, and leukemias (Sahai et al, 2016;Saenz et al, 2017;Xu & Vakoc, 2017;Sahni & Keri, 2018;Zhang et al, 2018;Baldan et al, 2019). Even though combined treatment with HDAC and BET inhibitors (BETi) revealed additive or synergistic effects in several cancer entities, such as cutaneous T-cell lymphoma, neuroblastoma, glioblastoma, non-small cell lung cancer, adenocarcinoma, and colon cancer (Mazur et al, 2015;Shahbazi et al, 2016;Adeegbe et al, 2017;Meng et al, 2018;Rajendran et al, 2019;Zhao et al, 2019), so far only few studies described the mono-and combined treatment options with BETis in GCTs.…”

Overcoming BET Inhibitor Resistance in Malignant Peripheral Nerve Sheath Tumors

“…S5A and S5B). Mice bearing xenograft tumors were then treated daily (including a 1-to 2-day drug holiday per mouse) with subcutaneous administration of vehicle or 30 mg/kg ARV771, a BET PROTAC with confirmed in vivo efficacy (56)(57)(58). We observed that this treatment regimen was well-tolerated in both cohorts ( Supplementary Fig.…”