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Sensitivity and Resistance to BH3 Mimetics in Cancer Therapy

  • Chapter
  • First Online:
Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 15))

  • 896 Accesses

Abstract

Targeted molecular agents have revolutionized cancer care in the adult population. Many of these drugs have been inhibitors of kinases. BCL-2 family members have long been understood to play key roles in mitochondrial integrity, serving as the key signaling nexus between kinase cascade-driven growth and survival signals, and they can also be found genetically altered in human cancers (e.g. IgG-BCL-2 translocations in follicular lymphoma). Indeed, the FDA-approval of the BCL-2 homology (BH)3 domain mimetic, venetoclax (AbbVie), is the first clinically approved BCL-2 family member targeted therapy of any kind, bringing BCL-2 family member inhibitors into the spotlight. This chapter will highlight the current state of affairs of this exciting time for BCL-2 family member targeted therapies, by focusing on three most advanced types of BCL-2 family inhibitors: the BCL-2 BH3 mimetic, venetoclax; the dual BCL-2/BCL-xL BH3 mimetic, navitoclax; and the recently developed MCL-1 BH3 mimetics. We will also discuss resistant mechanisms that have emerged from the intensification of preclinical and clinical studies of these compounds. The challenges understanding which cancers may most benefit from BH3 mimetics will also be discussed, as will the emergence of BH3 profling to address these challenges. Finally, we will discuss how these drugs may be combined with other currently available drugs to overcome resistance and induce robust clinical responses.

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Abbreviations

ALK:

Anaplastic lymphoma kinase

BAX:

BCL-2 associated X protein

BCL-2:

B cell-lymphoma 2

BH3:

BCL-2 homology 3

BIM:

BCL-2 interacting mediator of cell death

BRAF:

V-Raf murine sarcoma viral oncogene homolog B

EGFR:

Epidermal growth factor receptor

HER2:

Proto-oncogene Neu

MCL-1:

Myeloid cell leukemia-1

MEK:

Mitogen-activated protein kinase kinase

MOMP:

Mitochondrial Outer Membrane Permeabilization

mTOR:

Mechanistic target of repamycin

MYCN:

V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog

PI3K:

Phosphoinositide 3-kinase

PUMA:

p53 upregulated modulator of apoptosis

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Acknowledgments

This review was partly funded by NIH/NCI grant 5K22CA175276 (ACF), an American Cancer Society Research Scholar Grant (ACF), and a Massey Cancer Center Pilot grant (HH and ACF).

Conflict of Interest

No potential conflicts of interest were disclosed.

Note added in proof

We recently published that venetoclax is effective in small cell lung cancer with high BCL-2 expression [168], which, for the first time, demonstrates the eff ect of venetoclax in solid tumors.

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  1. Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA, 23298, USA

    Konstantinos V. Floros, Anthony C. Faber & Hisashi Harada

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  1. Konstantinos V. Floros
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  2. Anthony C. Faber
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Correspondence to Anthony C. Faber .

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  1. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Yosef Yarden

  2. Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheeva, Israel

    Moshe Elkabets

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Floros, K.V., Faber, A.C., Harada, H. (2018). Sensitivity and Resistance to BH3 Mimetics in Cancer Therapy. In: Yarden, Y., Elkabets, M. (eds) Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways. Resistance to Targeted Anti-Cancer Therapeutics, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-67932-7_7

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