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Dasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph+ acute lymphoblastic leukemia (ALL), but its efficacy is limited by resistance. Recent preclinical studies suggest that dasatinib may be a candidate therapy in additional ALL subtypes including pre-BCR+ ALL. Here we utilized shRNA library screening and global transcriptomic analysis to identify several novel genes and pathways that may enhance dasatinib efficacy or mitigate potential resistance in human pre-BCR+ ALL. Depletion of the transcriptional coactivator CBP increased dasatinib sensitivity by downregulating transcription of the pre-BCR signaling pathway previously associated with dasatinib sensitivity. Acquired resistance was due, in part, to upregulation of alternative pathways including WNT through a mechanism, suggesting transcriptional plasticity. Small molecules that disrupt CBP interactions with the CREB KID domain or β-catenin showed promising preclinical efficacy in combination with dasatinib. These findings highlight novel modulators of sensitivity to targeted therapies in human pre-BCR+ ALL, which can be reversed by small-molecule inhibitors. They also identify promising therapeutic approaches to ameliorate dasatinib sensitivity and prevent resistance in ALL. Significance: These findings reveal mechanisms that modulate sensitivity to dasatinib and suggest therapeutic strategies to improve the outcome of patients with acute lymphoblastic leukemia. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/22/6497/F1.large.jpg. Cancer Res; 78(22); 6497–508. ©2018 AACR.

Dasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph+ acute lymphoblastic leukemia (ALL), but its efficacy is limited by resistance. Recent preclinical studies suggest that dasatinib may be a candidate therapy in additional ALL subtypes including pre-BCR+ ALL. Here we utilized shRNA library screening and global transcriptomic analysis to identify several novel genes and pathways that may enhance dasatinib efficacy or mitigate potential resistance in human pre-BCR+ ALL. Depletion of the transcriptional co-activator CBP increased dasatinib sensitivity by downregulating transcription of the pre-BCR signaling pathway previously associated with dasatinib sensitivity. Acquired resistance was due in part to upregulation of alternative pathways including WNT through a mechanism suggesting transcriptional plasticity. Small molecules that disrupt CBP interactions with the CREB KID domain or β-catenin showed promising preclinical efficacy in combination with dasatinib. These findings highlight novel modulators of sensitivity to targeted therapies in human pre-BCR+ ALL, which can be reversed by small molecules inhibitors. They also identify promising therapeutic approaches to ameliorate dasatinib sensitivity and prevent resistance in ALL.

There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5%–7% of pediatric and 50% of pre-B-cell receptor (preBCR+) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL, which results in hyperactivation of the key oncogenic effector enzyme PLCγ2. Depletion of PLCγ2 reduced proliferation of mouse and human ALLs, including E2A-PBX1 leukemias, and increased disease-free survival after secondary transplantation. Mechanistically, E2A-PBX1 bound promoter regulatory regions and activated the transcription of its key target genes ZAP70, SYK, and LCK, which encode kinases upstream of PLCγ2. Depletion of the respective upstream kinases decreased cell proliferation and phosphorylated levels of PLCγ2 (pPLCγ2). Pairwise silencing of ZAP70, SYK, or LCK showed additive effects on cell growth inhibition, providing a rationale for combination therapy with inhibitors of these kinases. Accordingly, inhibitors such as the SRC family kinase (SFK) inhibitor dasatinib reduced pPLCγ2 and inhibited proliferation of human and mouse preBCR+/E2A-PBX1+ leukemias in vitro and in vivo. Furthermore, combining small-molecule inhibition of SYK, LCK, and SFK showed synergistic interactions and preclinical efficacy in the same setting. Our results show how the oncogenic fusion protein E2A-PBX1 perturbs signaling pathways upstream of PLCγ2 and renders leukemias amenable to targeted therapeutic inhibition. Cancer Res; 76(23); 6937–49. ©2016 AACR.

Background: PIK3CA, a gene that encodes the α-isoform of the catalytic subunit of Class I PI3K (PI3Kα), is frequently mutated or amplified in solid tumors. Taselisib is an oral, potent, selective inhibitor of Class I PI3Kα, γ, and δ isoforms with enhanced activity against PIK3CA-mutated cancer models. Preclinical and clinical data demonstrated that single-agent taselisib has activity in multiple PIK3CA-mutated tumor types. Methods: This open-label phase I study (Cohort X of PMT4979g; NCT01296555) enrolled patients (pts) with PIK3CA-mutated tumors who had progressed after, or failed to respond to, at least one prior treatment regimen and were not candidates for regimens known to provide clinical benefit. Pts received single-agent taselisib (4 or 6 mg tablet, daily). Eleven subcohorts comprised various solid tumor types: endometrial, bladder, head and neck squamous cell carcinoma (HNSCC), cervical, gastric/gastroesophageal junction, small cell lung, triple-negative breast, colorectal (excluding KRAS-mutated tumors), squamous (excluding histologies in the other subcohorts), ovarian, and pts with PIK3CA mutant tumors not otherwise specified (excluding breast, colorectal, and non-small-cell lung cancers). Tumor tissue (archival or fresh) was assessed centrally for PIK3CA mutation or amplification. The primary endpoint was tolerability and safety of taselisib. Other endpoints included assessment of antitumor activity per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Results: At data cutoff (May 1, 2017), 146 pts have been enrolled. Overall, the most common adverse events (AEs; ≥30% of pts) were diarrhea (58.2%), nausea (39.0%), hyperglycemia (31.5%), and fatigue (30.8%). Ninety-four pts (64.4%) experienced ≥1 grade ≥3 AE and 53 pts (36.3%) had grade ≥3 AEs related to taselisib. Sixty-eight pts (46.6%) had serious AEs (SAEs) and the most common SAEs (>2 pts) related to taselisib treatment were colitis (5.5%), diarrhea (4.1%), and hyperglycemia (3.4%). Nine pts (6.2%) had grade 5 events; one AE with a fatal outcome (0.7%) was assessed by the investigator as related to taselisib (septic shock). AEs that led to dose reduction, interruption, or withdrawal were reported in 34 pts (23.3%), 59 pts (40.4%), and 14 pts (9.6%), respectively. Overall, confirmed response rates were 8.9% (n=13) and clinical benefit rates (confirmed response or without disease progression for ≥6 months) were 12.3% (n=18). Confirmed responses were observed in pts with endometrial cancer (2/10 [20.0%]), HNSCC (4/21 [19.0%]), and cervical cancer (2/19 [10.5%]), as well as other tumor types. Conclusions: Single-agent taselisib had an acceptable safety profile (with AEs that were generally reversible and manageable; no new safety signals were identified) and preliminary clinical activity in pts with PIK3CA-mutated locally advanced or metastatic solid tumors. Citation Format: Komal Jhaveri, Dejan Juric, Cristina Saura, Andrés Cervantes, Anton Melnyk, Manish R. Patel, Mafalda Oliveira, Valentina Gambardella, Vincent Ribrag, Cynthia X. Ma, Raid Aljumaily, Philippe L. Bedard, Jasgit C. Sachdev, John Bond, Surai Jones, Timothy R. Wilson, Michael C. Wei, José Baselga. A phase I basket study of the PI3K inhibitor taselisib (GDC-0032) in PIK3CA-mutated locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT046.