Rationale for Combining the BCL2 Inhibitor Venetoclax with the PI3K Inhibitor Bimiralisib in the Treatment of IDH2- and FLT3-Mutated Acute Myeloid Leukemia.

Seipel, Katja; Brügger, Yvo; Mandhair, Harpreet; Bacher, Ulrike; Pabst, Thomas (2022). Rationale for Combining the BCL2 Inhibitor Venetoclax with the PI3K Inhibitor Bimiralisib in the Treatment of IDH2- and FLT3-Mutated Acute Myeloid Leukemia. International journal of molecular sciences, 23(20) MDPI 10.3390/ijms232012587

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In October 2020, the FDA granted regular approval to venetoclax (ABT-199) in combination with hypomethylating agents for newly-diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or in patients with comorbidities precluding intensive chemotherapy. The treatment response to venetoclax combination treatment, however, may be short-lived, and leukemia relapse is the major cause of treatment failure. Multiple studies have confirmed the upregulation of the anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family and the activation of intracellular signaling pathways associated with resistance to venetoclax. To improve treatment outcome, compounds targeting anti-apoptotic proteins and signaling pathways have been evaluated in combination with venetoclax. In this study, the BCL-XL inhibitor A1331852, MCL1-inhibitor S63845, dual PI3K-mTOR inhibitor bimiralisib (PQR309), BMI-1 inhibitor unesbulin (PTC596), MEK-inhibitor trametinib (GSK1120212), and STAT3 inhibitor C-188-9 were assessed as single agents and in combination with venetoclax, for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. Enhanced cytotoxic effects were present in all combination treatments with venetoclax in AML cell lines and AML patient samples. Elevated in vitro efficacies were observed for the combination treatment of venetoclax with A1331852, S63845 and bimiralisib, with differing response markers for each combination. For the venetoclax and bimiralisib combination treatment, responders were enriched for IDH2 and FLT3 mutations, whereas non-responders were associated with PTPN11 mutations. The combination of PI3K/mTOR dual pathway inhibition with bimiralisib and BCL2 inhibition with venetoclax has emerged as a candidate treatment in IDH2- and FLT3-mutated AML.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hämatologie / Onkologie (Pädiatrie)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hämatologie / Onkologie (Pädiatrie)

UniBE Contributor:

Seipel, Katja, Brügger, Yvo Andreas, Bacher, Vera Ulrike, Pabst, Thomas Niklaus

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1422-0067

Publisher:

MDPI

Language:

English

Submitter:

Pubmed Import

Date Deposited:

28 Oct 2022 13:49

Last Modified:

05 Dec 2022 16:27

Publisher DOI:

10.3390/ijms232012587

PubMed ID:

36293442

Uncontrolled Keywords:

B-cell lymphoma-2 (BCL2) Fms-related receptor tyrosine kinase 3 (FLT3) acute myeloid leukemia (AML) bimiralisib (PQR309) isocitrate dehydrogenase 2 (IDH2) mammalian target of rapamycin (mTOR) phosphoinositide 3-kinase (PI3K) protein tyrosine phosphatase non-receptor type 11 (PTPN11) venetoclax (ABT-199)

BORIS DOI:

10.48350/174216

URI:

https://boris.unibe.ch/id/eprint/174216

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