Selective drug combination vulnerabilities in STAT3- and TP53-mutant malignant NK cells

Abstract

Mature natural killer (NK) cell neoplasms are rare but very aggressive types of cancers. With currently available treatments, they have a very poor prognosis and, as such, are an example of group of cancers in which the development of effective precision therapies is needed. Using both short- and long-term drug sensitivity testing, we explored novel ways to target NK-cell neoplasms by combining the clinically approved JAK inhibitor ruxolitinib with other targeted agents. We profiled 7 malignant NK-cell lines in drug sensitivity screens and identified that these exhibit differential drug sensitivities based on their genetic background. In short-term assays, various classes of drugs combined with ruxolitinib seemed highly potent. Strikingly, resistance to most of these combinations emerged rapidly when explored in long-term assays. However, 4 combinations were identified that selectively eradicated the cancer cells and did not allow for development of resistance: ruxolitinib combined with the mouse double-minute 2 homolog (MDM2) inhibitor idasanutlin in STAT3-mutant, TP53 wild-type cell lines; ruxolitinib combined with the farnesyltransferase inhibitor tipifarnib in TP53-mutant cell lines; and ruxolitinib combined with either the glucocorticoid dexamethasone or the myeloid cell leukemia-1 (MCL-1) inhibitor S63845 but both without a clear link to underlying genetic features. In conclusion, using a new drug sensitivity screening approach, we identified drug combinations that selectively target mature NK-cell neoplasms and do not allow for development of resistance, some of which can be applied in a genetically stratified manner.

A lineage-specific STAT5BN642H mouse model to study NK-cell leukemia

“…To investigate the oncogenic potential of STAT5B N642H in NK cells, we ectopically expressed human STAT5B or STATB N642H in 2 human NK-cell lines (IMC-1 and KHYG-1) that harbor TP53 mutations but lack mutations in the JAK/STAT3/5 pathway. 40 , 60 Transduction with STAT5B or STAT5B N642H decreased cell growth in standard IL-2 culture (100 U/mL) but gave a growth advantage at limited IL-2 concentrations (25 U/mL; supplemental Figure 3 A-F). In the absence of IL-2, STAT5B N642H was required for cytokine-independent growth ( Figure 3 A-B; supplemental Figure 3C,F).…”

A lineage-specificSTAT5BN642Hmouse model to study NK-cell leukemia

“…Despite the presence of an activating STAT5B mutation, N642H vav/+ mice did not develop NK-cell leukemia. To investigate the oncogenic potential of STAT5B N642H in NK cells, we ectopically expressed human STAT5B or STATB N642H in two human NK-cell lines (IMC-1 and KHYG-1) that harbor TP53 mutations but lack mutations in the JAK/STAT3/5 pathway 33,53 . Transduction with STAT5B or STAT5B N642H decreased cell growth in standard IL-2 culture (100U/ml) ( Figure S3A+B ) but gave a growth advantage at limited IL-2 concentrations (25U/ml) ( Figure S3C+D ).…”

“…Despite the presence of an activating STAT5B mutation, N642H vav/+ mice did not develop NKcell leukemia. To investigate the oncogenic potential of STAT5B N642H in NK cells, we ectopically expressed human STAT5B or STATB N642H in two human NK-cell lines (IMC-1 and KHYG-1) that harbor TP53 mutations but lack mutations in the JAK/STAT3/5 pathway 33,53 .…”

Rational Targets of Therapy in Extranodal NK/T-Cell Lymphoma

“…Although no patients with ENKTL were included, this study provides a strong clinical rationale for the use of ruxolitinib and other JAK/STAT inhibitors in ENKTL cases with JAK/STAT aberrations and suggests that a biomarker-based therapeutic approach utilizing the aforementioned TSIM, MB, and HEA subtypes may be warranted. Further, in vitro studies suggest that ruxolitinib may be combined with novel TP53-MDM2 inhibitors in TP53-wild type disease, farnesyltransferase inhibitors in TP53-mutated disease, and with dexamethasone or novel MCL-1 inhibitors [52], or with the BCL2 inhibitor venetoclax or aurora kinase inhibitor alisertib in another study [53], to maximize activity and avoid long-term resistance.…”