TY - JOUR

T1 - Selective drug combination vulnerabilities in STAT3- And TP53-mutant malignant NK cells

AU - Parri, Elina

AU - Kuusanmäki, Heikki

AU - Bulanova, Daria

AU - Mustjoki, Satu

AU - Wennerberg, Krister

N1 - Funding Information: This work was supported through a center grant from the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology [DanStem], Grant Number NNF17CC0027852), grants from the Academy of Finland (277293 [K.W.] and 331256 [S.M.]), Sigrid Jusélius Foundation, Cancer Society of Finland, Finnish

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85104561828&partnerID=8YFLogxK

U2 - 10.1182/BLOODADVANCES.2020003300

DO - 10.1182/BLOODADVANCES.2020003300

M3 - Journal article

C2 - 33792631

AN - SCOPUS:85104561828

VL - 5

SP - 1862

EP - 1875

JO - Blood advances

JF - Blood advances

SN - 2473-9529

IS - 7

ER -