Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer

Faber, Anthony C.; Farago, Anna F.; Costa, Carlotta; Dastur, Anahita; Gomez‐Caraballo, María; Robbins, Rebecca; Wagner, Bethany L.; Rideout, William M.; Jakubik, Charles T.; Ham, Jungoh; Edelman, Elena J.; Ebi, Hiromichi; Yeo, Alan T.; Hata, Aaron N.; Song, Youngchul; Patel, Neha U.; March, Ryan J.; Tam, Ah Ting; Milano, Randy; Boisvert, Jessica L.; Hicks, Mark; Elmiligy, Sarah; Malstrom, Scott; Rivera, Miguel N.; Harada, Hisashi; Windle, Brad E.; Ramaswamy, Sridhar; Benes, Cyril H.; Jacks, Tyler; Engelman, Jeffrey A.

doi:10.1073/pnas.1411848112

Cited by 109 publications

(127 citation statements)

References 46 publications

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“…BAX protein levels were not decreased in H1048, H526, or DMS114 cells after treatment with PI3K pathway inhibitors (PI-103, MK-2206, or KU-0063794) in our study ( Supplementary Fig. S4A), consistent with observations of Faber and colleagues in H1048 cells and in a PDX model using the TORC1/2 inhibitor AZD8055 (39). Moreover, we saw no synergy in H146 cells treated with ABT-737 plus any of the PI3K pathway inhibitors we examined.…”

Section: Discussionsupporting

confidence: 92%

“…Our study with that of Gardner and colleagues (52) and Faber and colleagues (39) suggest that there are different mechanisms downstream of PI3K signaling that suppress BH3 mimeticinduced apoptosis; we introduce a new component, BMX, that acts downstream of PI3K and upstream of Bcl-2 family gatekeepers of apoptosis. Overall, despite cell line and pathway inhibitor-dependent differential mechanisms, the efficacy of GDC-0941 and Navitoclax in a CDX model derived from a chemorefractory patient highlights the potential clinical utility of this combination and strongly supports initiation of a clinical trial with a BH3 mimetic and a PI3K pathway inhibitor in SCLC patients.…”

Section: Discussionmentioning

confidence: 63%

“…MCL-1 is an established resistance factor of ABT-737 and Navitoclax efficacy (22,23) and is downregulated by mTOR signaling leading to Navitoclax sensitization (39). Although PI3K pathway inhibitors did not downregulate MCL-1 in H1048 cells (Fig.…”

Section: Pi-103 Sensitizes To Abt-737 Independent Of Mcl-1mentioning

confidence: 93%

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Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo. These data add to a body of evidence that this combination should move toward the clinic.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 63%

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Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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“…It shows that AZD8055-induced mTOR inhibition decreases Mcl-1 expression by more than half in two of three ovarian cancer cell lines, which is consistent with results obtained in other cancer cell types (39)(40)(41)(42). This decrease may be ascribed inhibition.…”

Section: Discussionsupporting

confidence: 89%

The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737

Pétigny-Lechartier

Duboc

Jebahi

et al. 2017

Molecular Cancer Therapeutics

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The identification of novel therapeutic strategies is an important urgent requirement for the clinical management of ovarian cancer, which remains the leading cause of death from gynecologic cancer. Several studies have shown that the antiapoptotic proteins Bcl-x L and Mcl-1, as well as the proapoptotic protein Bim, are key elements to be modulated to kill ovarian cancer cells. Pharmacologic inhibition of Bcl-x L is possible by using BH3-mimetic molecules like ABT-737. However, inhibition of Mcl-1 and/or promotion of its BH3-only partners (including Bim, Puma, and Noxa) remains a challenge that may be achieved by modulating the signaling pathways upstream. This study sought whether AZD8055-induced mTOR inhibition and/or trametinibinduced MEK inhibition could modulate Mcl-1 and its partners to decrease the Mcl-1/BH3-only ratio and thus sensitize various ovarian cancer cell lines to ABT-737. AZD8055 treatment inhibited Mcl-1 and increased Puma expression but did not induce massive apoptosis in combination with ABT-737. In contrast, trametinib, which decreased the Mcl-1/BH3-only protein ratio by upregulating Puma and dephosphorylated active Bim, sensitized IGROV1-R10 and OVCAR3 cells to ABT-737. Adding AZD8055 to trametinib further reduced the Mcl-1/BH3-only protein ratio and triggered apoptosis without ABT-737 in IGROV1-R10 cells. Moreover, the AZD8055/trametinib association highly sensitized all cell lines including SKOV3 to ABT-737, the induced dephosphorylated Bim being crucial in this sensitization. Finally, the three-drug combination was also very efficient when replacing AZD8055 by the pan-Akt inhibitor MK-2206. This study thus proposes original multitargeted strategies and may have important implications for the design of novel approaches for ovarian cancer treatment. Mol Cancer Ther; 16(1); 102-15. Ó2016 AACR.

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“…ABT-263 treatment induced a robust apoptotic response in EGFR-mutant SCLC compared with the resistant EGFRmutant NSCLC. The gene expression and drug sensitivity of the SCLC-transformed cells more closely resemble classical SCLC than EGFR-mutant NSCLC (73).…”

Section: Mechanisms Of Acquired Resistance To Targeted Cancer Therapiesmentioning

confidence: 94%

Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors

Dorantes-Heredia¹,

Ruíz-Morales²,

Cano-García³

2016

Transl. Lung Cancer Res.

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Lung cancer is the principal cause of cancer-related death worldwide. The use of targeted therapies, especially tyrosine kinase inhibitors (TKIs), in specific groups of patients has dramatically improved the prognosis of this disease, although inevitably some patients will develop resistance to these drugs during active treatment. The most common cancer-associated acquired mutation is the epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation. During active treatment with targeted therapies, histopathological transformation to small-cell lung carcinoma (SCLC) can occur in 3-15% of patients with non-small-cell lung carcinoma (NSCLC) tumors. By definition, SCLC is a high-grade tumor with specific histological and genetic characteristics. In the majority of cases, a good-quality hematoxylin and eosin (H&E) stain is enough to establish a diagnosis. Immunohistochemistry (IHC) is used to confirm the diagnosis and exclude other neoplasia such as sarcomatoid carcinomas, large-cell carcinoma, basaloid squamous-cell carcinoma, chronic inflammation, malignant melanoma, metastatic carcinoma, sarcoma, and lymphoma. A loss of the tumor-suppressor protein retinoblastoma 1 (RB1) is found in 100% of human SCLC tumors; therefore, it has an essential role in tumorigenesis and tumor development. Other genetic pathways probably involved in the histopathological transformation include neurogenic locus notch homolog (NOTCH) and achaete-scute homolog 1 (ASCL1). Histological transformation to SCLC can be suspected in NSCLC patients who clinically deteriorate during active treatment. Biopsy of any new lesion in this clinical setting is highly recommended to rule out a SCLC transformation. New studies are trying to assess this histological transformation by noninvasive measures such as measuring the concentration of serum neuronspecific enolase.

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Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer

Cited by 109 publications

References 46 publications

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737

Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors

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