Emerging role of MYB transcription factors in cancer drug resistance

Abstract

Decades ago, the viral myeloblastosis oncogene v-myb was identified as a gene responsible for the development of avian leukemia. However, the relevance of MYB proteins for human cancer diseases, in particular for solid tumors, remained basically unrecognized for a very long time. The human family of MYB transcription factors comprises MYB (c-MYB), MYBL2 (b-MYB), and MYBL1 (a-MYB), which are overexpressed in several cancers and are associated with cancer progression and resistance to anticancer drugs. In addition to overexpression, the presence of activated MYB-fusion proteins as tumor drivers was described in certain cancers. The identification of anticancer drug resistance mediated by MYB proteins and their underlying mechanisms are of great importance in understanding failures of current therapies and establishing new and more efficient therapy regimens. In addition, new drug candidates targeting MYB transcription factor activity and signaling have emerged as a promising class of potential anticancer therapeutics that could tackle MYB-dependent drug-resistant cancers in a more selective way. This review describes the correlation of MYB transcription factors with the formation and persistence of cancer resistance to various approved and investigational anticancer drugs.

Keywords: Anticancer drugs; MYB; MYB-targeting drugs; cancer resistance mechanisms; drug resistance; oncogenes; transcription factors.

Figure 1

Gene transcription regulated by MYB, MYBL2, and MYB fusions (e.g., MYB-NFIB) plays a crucial role in the resistance to DNA-targeting, microtubule-targeting and nuclear receptor-targeting drugs, as well as to targeted therapy, HDACi, and checkpoint inhibitors. MYB proteins were associated with suppressed cell death and promotion of cell proliferation and survival. Resistance to DNA-targeting drugs includes platinum complexes, topoisomerase inhibitors, antimetabolites, PARP inhibitors, alkylating and photodynamic drugs. Microtubule-targeting drugs include vinca alkaloids and taxanes. Resistance to nuclear receptors refers to activators of GR and RAR, as well as inhibitors of AR and ER. Resistance to targeted therapy includes inhibitors of RTKs with implications for oncogenic Ras-MAPK and PI3K-AKT signaling, inhibitors of JAK-STAT signaling, as well as inhibitors of BCR/ABL tyrosine kinase and CHK. Resistance to epigenetic drugs and checkpoint inhibitors includes HDACi and anti-PD-1 antibodies. NFIB: Nuclear factor IB; HDACi: histone deacetylase inhibitors; PARP: phthalazinone-based poly (ADP-ribose) polymerase; GR: glucocorticoid receptor; RAR: retinoic acid receptor; AR: androgen receptors; ER: estrogen receptors; RTKs: receptor tyrosine kinases; MAPK: mitogen-activated protein kinase; PI3K: phosphoinositide 3 kinase; AKT: protein kinase B; JAK: Janus kinase; STAT: signal transduction activator of transcription; BCR: breakpoint cluster region protein; CHK: checkpoint kinase; PD-1: programmed death 1.

Figure 2

Structures of VEGFR-targeting (multi-)kinase inhibitors (targets in brackets) with effects on MYB activity and/or MYB-dependent cancers. VEGFR: Vascular endothelial growth factor receptor.

Figure 3

Structures of inhibitors of PI3K-AKT-mTOR signaling (kinase targets in brackets) with effects on MYB activity and/or MYB-dependent cancers (green: mechanisms; red: targeted cancers). PI3K: Phosphoinositide 3 kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin.

Figure 4

Structures of miscellaneous protein kinase inhibitors (kinase targets in brackets) with effects on MYB activity and/or MYB-dependent cancers (green: mechanisms; red: targeted cancers).

Figure 5

Structures of CDK inhibitors and the IGF-1R inhibitor linsitinib with effects on MYB activity and/or MYB-dependent cancers (green: mechanisms; red: targeted cancers). CDK: Cyclin-dependent kinase; IGF-1R: insulin-like growth factor 1 receptor.

Figure 6

Structures of epigenetic drugs (targets in brackets) with effects on MYB activity and/or MYB-dependent cancers (green: mechanisms; red: targeted cancers).

Figure 7

Structures of transcription factor modulators and MYB promoter G-quadruplex binders (targets in brackets) with effects on MYB activity and/or MYB-dependent cancers (green: mechanisms; red: targeted cancers).

Figure 8

Structures of natural products (arranged according to compound classes) with inhibitory effects on MYB activity (for the terpenoids RA/ATRA, calcitriol, and steroids dexamethasone and estradiol, as well as the alkaloids camptothecin and topotecan see Figure 7; green: mechanisms; red: targeted cancers). RA: Retinoic acid; ATRA: all-trans retinoic acid.

Figure 9

Structures of small-molecule di/trimethoxyphenyl- and amide/peptide-based inhibitors (polypeptides were omitted for clarity) and repurposed drugs with inhibitory effects on MYB activity (green: mechanisms; red: targeted cancers).