Data from Dual targeting of apoptotic and signaling pathways in T-lineage acute lymphoblastic leukemia Article Swipe

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Caner Saygin , Giorgia Giordano , Kathryn Shimamoto , Bart Eisfelder , Anika T. Thomas-Toth , Girish Venkataraman , Vijayalakshmi Ananthanarayanan , Tiffaney L. Vincent , Adam DuVall , Anand Patel , Yi Chen , Fenlai Tan , Stephen P. Anthony , Yu Chen , Yue Shen , Olatoyosi Odenike , David T. Teachey , Barbara L. Kee , James L. LaBelle , Wendy Stock ·

YOU? · · 2024 · Open Access · · DOI: https://doi.org/10.1158/1078-0432.c.6740540.v5

Purpose: Relapsed T-acute lymphoblastic leukemia (T-ALL) has limited treatment options. We investigated mechanisms of resistance to BH3 mimetics in T-ALL in order to develop rational combination strategies. We also looked at the preclinical efficacy of NWP-0476, a novel BCL-2/BCL-xL inhibitor, as single agent and combination therapy in T-ALL. Methods: We used BH3 profiling as a predictive tool for BH3 mimetic response in T-ALL. Using isogenic control, venetoclax-resistant (ven-R) and NWP-0476-resistant (NWP-R) cells, phosphokinase array was performed to identify differentially regulated signaling pathways. Results: Typical T-ALL cells had increased dependence on BCL-xL, while early T-precursor (ETP)-ALL cells had higher BCL-2 dependence for survival. BCL-2/BCL-xL dual inhibitors were effective against both subtypes of T-lineage ALL. A 71-protein human phosphokinase array showed increased LCK activity in ven-R cells, and increased ACK1 activity in ven-R and NWP-R cells. We hypothesized that pre-TCR and ACK1 signaling pathways are drivers of resistance to BCL-2 and BCL-xL inhibition, respectively. First, we silenced LCK gene in T-ALL cell lines, which resulted in increased sensitivity to BCL-2 inhibition. Mechanistically, LCK activated NF-κB pathway and the expression of BCL-xL. Silencing ACK1 gene resulted in increased sensitivity to both BCL-2 and BCL-xL inhibitors. ACK1 signaling up-regulated AKT pathway, which inhibited the pro-apoptotic function of BAD. In a T-ALL patient-derived xenograft model, combination of NWP-0476 and dasatinib demonstrated synergy without major organ toxicity. Conclusions:LCK and ACK1 signaling pathways are critical regulators of BH3 mimetic resistance in T-ALL. Combination of BH3 mimetics with tyrosine kinase inhibitors might be effective against relapsed T-ALL.

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Acute Lymphoblastic Leukemia

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Lymphoblastic Leukemia Lineage (genetic) Cancer research Apoptosis Dual (grammatical number) Signal transduction Leukemia Medicine Biology Immunology Cell biology Genetics Gene Literature Art

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Type: preprint
Language: en
Landing Page: https://doi.org/10.1158/1078-0432.c.6740540.v5
OA Status: gold
Related Works: 10
OpenAlex ID: https://openalex.org/W4402818171

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DOI: https://doi.org/10.1158/1078-0432.c.6740540.v5

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Title: Data from Dual targeting of apoptotic and signaling pathways in T-lineage acute lymphoblastic leukemia

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Type: preprint

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Language: en

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Publication year: 2024

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Publication date: 2024-09-16

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Authors: Caner Saygin, Giorgia Giordano, Kathryn Shimamoto, Bart Eisfelder, Anika T. Thomas-Toth, Girish Venkataraman, Vijayalakshmi Ananthanarayanan, Tiffaney L. Vincent, Adam DuVall, Anand Patel, Yi Chen, Fenlai Tan, Stephen P. Anthony, Yu Chen, Yue Shen, Olatoyosi Odenike, David T. Teachey, Barbara L. Kee, James L. LaBelle, Wendy Stock

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Landing page: https://doi.org/10.1158/1078-0432.c.6740540.v5

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OA status: gold

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Concepts: Lymphoblastic Leukemia, Lineage (genetic), Cancer research, Apoptosis, Dual (grammatical number), Signal transduction, Leukemia, Medicine, Biology, Immunology, Cell biology, Genetics, Gene, Literature, Art

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abstract_inverted_index.activity	121, 128
abstract_inverted_index.control,	65
abstract_inverted_index.critical	227
abstract_inverted_index.efficacy	33
abstract_inverted_index.function	201
abstract_inverted_index.identify	77
abstract_inverted_index.isogenic	64
abstract_inverted_index.leukemia	4
abstract_inverted_index.mimetics	17, 238
abstract_inverted_index.options.	9
abstract_inverted_index.pathway,	196
abstract_inverted_index.pathways	141, 225
abstract_inverted_index.rational	24
abstract_inverted_index.relapsed	247
abstract_inverted_index.response	60
abstract_inverted_index.resulted	162, 182
abstract_inverted_index.silenced	154
abstract_inverted_index.subtypes	109
abstract_inverted_index.tyrosine	240
abstract_inverted_index.(ETP)-ALL	94
abstract_inverted_index.NWP-0476,	35
abstract_inverted_index.Silencing	179
abstract_inverted_index.T-lineage	111
abstract_inverted_index.activated	171
abstract_inverted_index.dasatinib	214
abstract_inverted_index.effective	106, 245
abstract_inverted_index.increased	87, 119, 126, 164, 184
abstract_inverted_index.inhibited	198
abstract_inverted_index.pathways.	81
abstract_inverted_index.performed	75
abstract_inverted_index.profiling	52
abstract_inverted_index.regulated	79
abstract_inverted_index.signaling	80, 140, 193, 224
abstract_inverted_index.survival.	101
abstract_inverted_index.toxicity.	220
abstract_inverted_index.treatment	8
abstract_inverted_index.xenograft	208
abstract_inverted_index.71-protein	114
abstract_inverted_index.dependence	88, 99
abstract_inverted_index.expression	176
abstract_inverted_index.inhibitor,	39
abstract_inverted_index.inhibitors	104, 242
abstract_inverted_index.mechanisms	12
abstract_inverted_index.predictive	55
abstract_inverted_index.regulators	228
abstract_inverted_index.resistance	14, 145, 232
abstract_inverted_index.Combination	235
abstract_inverted_index.T-precursor	93
abstract_inverted_index.combination	25, 44, 210
abstract_inverted_index.inhibition,	150
abstract_inverted_index.inhibition.	168
abstract_inverted_index.inhibitors.	191
abstract_inverted_index.preclinical	32
abstract_inverted_index.sensitivity	165, 185
abstract_inverted_index.strategies.	26
abstract_inverted_index.BCL-2/BCL-xL	38, 102
abstract_inverted_index.demonstrated	215
abstract_inverted_index.hypothesized	135
abstract_inverted_index.investigated	11
abstract_inverted_index.up-regulated	194
abstract_inverted_index.lymphoblastic	3
abstract_inverted_index.phosphokinase	72, 116
abstract_inverted_index.pro-apoptotic	200
abstract_inverted_index.respectively.	151
abstract_inverted_index.differentially	78
abstract_inverted_index.Conclusions:LCK	221
abstract_inverted_index.patient-derived	207
abstract_inverted_index.Mechanistically,	169
abstract_inverted_index.NWP-0476-resistant	69
abstract_inverted_index.venetoclax-resistant	66
abstract_inverted_index.T-ALL.</p></div>	248
abstract_inverted_index.<div>Abstract<p>Purpose:	0
cited_by_percentile_year
countries_distinct_count	0
institutions_distinct_count	20
citation_normalized_percentile.value	0.27448317
citation_normalized_percentile.is_in_top_1_percent	False
citation_normalized_percentile.is_in_top_10_percent	False