Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia

Abstract

Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCRABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays, and hydrogen-deuterium exchange assays establish direct engagement of STAT3 by BP-5-087 and provide a high-resolution view of the STAT3 SH2 domain/BP-5-087 interface. In primary cells from CML patients with BCR-ABL1 kinase-independent TKI resistance, BP-5-087 (1.0 μM) restored TKI sensitivity to therapy-resistant CML progenitor cells, including leukemic stem cells (LSCs). Our findings implicate STAT3 as a critical signaling node in BCR-ABL1 kinase-independent TKI resistance, and suggest that BP-5-087 has clinical utility for treating malignancies characterized by STAT3 activation.

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…In contrast, specific targeting of a tumor suppressor to restore normal function has been reported but remains challenging. However, loss of tumor suppressors, such as SOCS2 or PRC2, leads to hyperactivation of the JAK-STAT pathway which could be targeted instead [8,9]. …”

“…This clinically challenging condition is often associated with further genetic aberrations in the driver itself (BCR-ABL1) or with mutations in other critical target genes. Moreover, epigenetic and other mechanisms may promote upregulation of the STAT3/5 pathway, allowing cancer cells to escape drug action [8]. Combining different therapies against multiple ‘oncogene addictions’ could be a possibility to overcome primary or acquired resistance.…”

“…More recently, a number of promising covalent STAT3/5 SH 2 domain-binding inhibitors have been described [8,133,134,152]. These compounds exhibit potent and selective binding activity for STAT3/5 by effectively disrupting phosphopeptide interactions.…”

“…The lead agent 13a suppresses STAT3/5 tyrosine phosphorylation and inhibits STAT3/5-mediated gene expression, including downregulation of MYC, Cyclin D1, Cyclin D2, and MCL-1 oncoproteins. Importantly, the dual inhibitory function of STAT3/5 inhibitors is of high clinical relevance since Imatinib-resistant CML cells upregulate and activate STAT3, which represents a major signaling node conferring TKI resistance [8]. Moreover, a feedback upregulation of STAT3 as a common cause of resistance to receptor TK/MEK-targeted therapy was described [153].…”

WP1066 exhibits antitumor efficacy in nasal-type natural killer/T-cell lymphoma cells through downregulation of the STAT3 signaling pathway

“…Constitutive activation of the STAT3 pathway has been noted in a wide range of cancers and typically occurs in response to stimulation by tumor-promoting factors, including epidermal growth factor, IL-6, Tyr kinase, and many others (21,22). Inhibition of aberrantly activated STAT3 signaling pathway may present a novel antitumor strategy (Fig.…”