Navitoclax Enhances the Efficacy of Taxanes in Non–Small Cell Lung Cancer Models

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To examine the potential of combining Bcl-2 family inhibitors with chemotherapy in ovarian cancer, we evaluated a panel of 27 ovarian cancer cell lines for response to the combination of navitoclax (formerly ABT-263) and paclitaxel or gemcitabine. The majority of cell lines exhibited a greater than additive response to either combination, as determined by the Bliss independence model, and more than 50% of the ovarian cell lines exhibited strong synergy for the navitoclax/paclitaxel combination. To identify biomarkers for tumors likely to respond to this combination, we evaluated the protein levels of intrinsic apoptosis pathway components. Bcl-x L seems necessary, but not sufficient, for navitoclax/paclitaxel synergy in vitro, suggesting that exclusion of patients whose tumors have low or undetectable Bcl-x L would enrich for patients responsive to the combination. We evaluated Bcl-x L levels in ovarian cancer tumor tissue from 40 patients (20 taxane responsive and 20 with poor response to taxane) and found that patients with high Bcl-x L were less sensitive to taxane treatment (10 of 12) Bcl-x L positive patients, P ¼ 0.014). These data support the use of navitoclax in combination with taxane-based therapy in ovarian cancer patients with high levels of Bcl-x L .

Section: Response To Inhibitor Treatmentmentioning

confidence: 76%

“…Thus, there is a need for strategies to improve the durability of response to chemotherapy in ovarian cancer. One strategy is to combine chemotherapy with an inhibitor of antiapoptotic Bcl-2 family proteins to increase cell death after cell-cycle arrest (3,4).…”

Section: Introductionmentioning

confidence: 99%

Navitoclax (ABT-263) Reduces Bcl-xL–Mediated Chemoresistance in Ovarian Cancer Models

Wong¹,

Tan²,

Zha³

et al. 2012

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“…Navitoclax has been shown to enhance the activity of chemotherapeutic agents (20)(21)(22)(23)(24). However, studies on its ability to enhance targeted therapy have been limited.…”

Section: Introductionmentioning

confidence: 99%

Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models

Tan¹,

Wong²,

Nannini³

et al. 2013

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Although mitogen-activated protein (MAP)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition is predicted to cause cell death by stabilization of the proapoptotic BH3-only protein BIM, the induction of apoptosis is often modest. To determine if addition of a Bcl-2 family inhibitor could increase the efficacy of a MEK inhibitor, we evaluated a panel of 53 non-small cell lung cancer and pancreatic cancer cell lines with the combination of navitoclax (ABT-263), a Bcl-2/Bcl-x L (BCL2/BCL2L1) antagonist, and a novel MAP kinase (MEK) inhibitor, G-963. The combination is synergistic in the majority of lines, with an enrichment of cell lines harboring KRAS mutations in the high synergy group. Cells exposed to G-963 arrest in G 1 and a small fraction undergo apoptosis. The addition of navitoclax to G-963 does not alter the kinetics of cell-cycle arrest, but greatly increases the percentage of cells that undergo apoptosis. The G-963/navitoclax combination was more effective than either single agent in the KRAS mutant H2122 xenograft model; BIM stabilization and PARP cleavage were observed in tumors, consistent with the mechanism of action observed in cell culture.

“…Navitoclax exhibits potent single-agent antitumor activity in multiple murine xenograft models of small cell lung cancer (SCLC), leukemia, and lymphoma (13,14) and, in addition, potentiates the activity of clinically relevant chemotherapeutic regimens, for example, rituximab, rapamycin, rituximabcyclophosphamide-Adriamycin-vincristine-prednisone (CHOP), and bortezomib, in several models of hematologic malignancies (14,15). However, the interrogation of the ability of navitoclax to enhance the activity of chemotherapeutic agents in solid tumors has been limited (16).…”

Section: Introductionmentioning

confidence: 99%

The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents In Vitro and In Vivo

Chen

Jin

Abraham

et al. 2011

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136

The ability of a cancer cell to avoid apoptosis is crucial to tumorigenesis and can also contribute to chemoresistance. The Bcl-2 family of prosurvival proteins (Bcl-2, Bcl-X L , Bcl-w, Mcl-1, and A1) plays a key role in these processes. We previously reported the discovery of ABT-263 (navitoclax), a potent small-molecule inhibitor of Bcl-2, Bcl-X L , and Bcl-w. While navitoclax exhibits single-agent activity in tumors dependent on Bcl-2 or Bcl-X L for survival, the expression of Mcl-1 has been shown to confer resistance to navitoclax, most notably in solid tumors. Thus, therapeutic agents that can downregulate or neutralize Mcl-1 are predicted to synergize potently with navitoclax. Here, we report the activity of navitoclax in combination with 19 clinically relevant agents across a panel of 46 human solid tumor cell lines. Navitoclax broadly enhanced the activity of multiple therapeutic agents in vitro and enhanced efficacy of both docetaxel and erlotinib in xenograft models. The ability of navitoclax to synergize with docetaxel or erlotinib corresponded to an altered sensitivity of the mitochondria toward navitoclax, which was associated with the downmodulation of Mcl-1 and/or upregulation of Bim. These data provide a rationale to interrogate these combinations clinically.