MA02.06 Phase 1b Study of Pelcitoclax (APG-1252) in Combination With Osimertinib in Patients With EGFR TKI-Resistant NSCLC

Zhang, L.; Zhao, Hongyun; Ma, Yuxiang; Cheng, Ying; Zhao, Yanqiu; Cui, Jiuwei; Yang, Cheng-Shu; Zhang, J.; Wang, P.; Xu, Lu; Yu, Justin; Men, Lichuang; Liang, Eric; Yang, Dong‐Hua; Zhai, Yifan

doi:10.1016/j.jtho.2021.08.115

Cited by 5 publications

(7 citation statements)

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“…In our study, we also validated the enhanced ability of the ABT-263 and osimertinib combination to decrease the survival of different osimertinib-resistant cell lines.Together, our data support the potential of targeting Bcl-2/Bcl-X L for overcoming acquired resistance to osimertinib and likely other third generation EGFR-TKIs. In fact, there is an ongoing phase 1b study of APG-1252 in combination with osimertinib in patients with EGFR TKIresistant NSCLC showing preliminary safety and efficacy (clinical trial registration: NCT04001777) 42. Once acquiring resistance to osimertinib, EGFRm cell lines become resistant to Mcl-1 modulation induced by osimertinib as we demonstrated previously 25.…”

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confidence: 65%

“…With the strategy of pro-drug design, APG1252 has limited cell permeability during circulation when given through the iv route and can be converted to the more active metabolite, APG-1252-M1, in tumors/tissues. This makes it distinct from other similar inhibitors in having a favorable platelet toxicity profile in patients as demonstrated in clinical trials 24,42. 5 | CONCLUSIONSThe current study has demonstrated the impact of Mcl-1 levels on the responses of NSCLC cells to APG1252-M1 and its potential monotherapy efficacy in a subset of NSCLC cells with low levels of Mcl-1.…”

mentioning

confidence: 66%

“…Together, our data support the potential of targeting Bcl‐2/Bcl‐X L for overcoming acquired resistance to osimertinib and likely other third generation EGFR‐TKIs. In fact, there is an ongoing phase 1b study of APG‐1252 in combination with osimertinib in patients with EGFR TKI‐resistant NSCLC showing preliminary safety and efficacy (clinical trial registration: NCT04001777) 42 …”

Section: Discussionmentioning

confidence: 99%

“…With the strategy of pro‐drug design, APG1252 has limited cell permeability during circulation when given through the iv route and can be converted to the more active metabolite, APG‐1252‐M1, in tumors/tissues. This makes it distinct from other similar inhibitors in having a favorable platelet toxicity profile in patients as demonstrated in clinical trials 24,42 …”

Section: Discussionmentioning

confidence: 99%

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Therapeutic potential of the novel Bcl‐2/Bcl‐X_L dual inhibitor, APG1252, alone or in combination against non‐small cell lung cancer

Qian

Vallega

Yao

et al. 2022

Molecular Carcinogenesis

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Targeting the induction of apoptosis is a promising cancer therapeutic strategy with some clinical success. This study focused on evaluating the therapeutic efficacy of the novel Bcl-2/Bcl-X L dual inhibitor, APG1252-M1 (also named APG-1244; an in vivo active metabolite of APG1252 or pelcitoclax), as a single agent or in combination, against non-small cell lung cancer (NSCLC) cells. APG1252-M1 effectively decreased the survival of some NSCLC cell lines expressing low levels of Mcl-1 and induced apoptosis. Overexpression of ectopic Mcl-1 in the sensitive cells substantially compromised APG1252-M1's cell-killing effects, whereas inhibition of Mcl-1 greatly sensitized insensitive cell lines to APG1252-M1, indicating the critical role of Mcl-1 levels in impacting cell response to APG1252-M1. Moreover, APG1252-M1, when combined with the third generation epidermal growth factor receptor (EGFR) inhibitor, osimertinib, synergistically decreased the survival of EGFR-mutant NSCLC cell lines including those resistant to osimertinib with enhanced induction of apoptosis and abrogated emergence of acquired resistance to osimertinib. Importantly, the combination was effective in inhibiting the growth of osimertinib-resistant tumors in vivo. Collectively, these results demonstrate the efficacy of APG1252 alone or in combination against human NSCLC cells.

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confidence: 65%

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confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Therapeutic potential of the novel Bcl‐2/Bcl‐X_L dual inhibitor, APG1252, alone or in combination against non‐small cell lung cancer

Qian

Vallega

Yao

et al. 2022

Molecular Carcinogenesis

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“…As so, it has limited cell permeability during circulation when given through iv route and will be converted to the more active metabolite, APG-1252-M1, once in tumors/tissues. This feature makes it a unique Bcl-2/Bcl-X L inhibitor with a favorable and manageable platelet toxicity profile in patients as demonstrated in clinical trials [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-XL dual inhibitor that induces Bax-dependent apoptosis

et al. 2022

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Strategies to Reduce the On‐Target Platelet Toxicity of Bcl‐x_L Inhibitors: PROTACs, SNIPERs and Prodrug‐Based Approaches

Negi

Voisin‐Chiret

2022

ChemBioChem

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Apoptosis is a highly regulated cellular process. Aberration in apoptosis is a common characteristic of various disorders. Therefore, proteins involved in apoptosis are prime targets in multiple therapies. Bcl-x L is an antiapoptotic protein. Compared to other antiapoptotic proteins, the expression of Bcl-x L is common in solid tumors and, to an extent, in some leukemias and lymphomas. The overexpression of Bcl-x L is also linked to survival and chemoresistance in cancer and senescent cells. Therefore, Bcl-x L is a promising anticancer and senolytic target. Various nanomolar range Bcl-x L inhibitors have been developed. ABT-263 was successfully identified as a Bcl-x L /Bcl-2 dual inhibitor. But it failed in the clinical trial (phase-II) because of its on-target platelet toxicity, which also implies an essential role of Bcl-x L protein in the survival of human platelets. Classical Bclx L inhibitor designs utilize occupancy-driven pharmacology with typical shortcomings (such as dose-dependent off-target and on-target platelet toxicities). Hence, event-driven pharmacology-based approaches, such as proteolysis targeting chimeras (PROTACs) and SNIPERs (specific non-genetic IAP-based protein erasers) have been developed. The development of Bclx L based PROTACs was expected, as 600 E3-ligases are available in humans, while some (such as cereblon (CRBN), von Hippel-Lindau (VHL)) are relatively less expressed in platelets. Therefore, E3 ligase ligand-based Bcl-x L PROTACs (CRBN: XZ424, XZ739; VHL: DT2216, PZ703b, 753b) showed a significant improvement in platelet therapeutic index than their parent molecules (ABT-263: DT2216, PZ703b, 753b, XZ739, PZ15227; A1155463: XZ424). Other than their distinctive pharmacology, PROTACs are molecularly large, which limits their cell permeability and plays a role in improving their cell selectivity. We also discuss prodrug-based approaches, such as antibody-drug conjugates (ABBV-155), phosphate prodrugs (APG-1252), dendrimer conjugate (AZD0466), and glycosylated conjugates (Nav-Gal). Studies of in-vitro, in-vivo, structure-activity relationships, biophysical characterization, and status of preclinical/ clinical inhibitors derived from these strategies are also discussed in the review.

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MA02.06 Phase 1b Study of Pelcitoclax (APG-1252) in Combination With Osimertinib in Patients With EGFR TKI-Resistant NSCLC

Cited by 5 publications

References 0 publications

Therapeutic potential of the novel Bcl‐2/Bcl‐X_L dual inhibitor, APG1252, alone or in combination against non‐small cell lung cancer

Therapeutic potential of the novel Bcl‐2/Bcl‐X_L dual inhibitor, APG1252, alone or in combination against non‐small cell lung cancer

Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-XL dual inhibitor that induces Bax-dependent apoptosis

Strategies to Reduce the On‐Target Platelet Toxicity of Bcl‐x_L Inhibitors: PROTACs, SNIPERs and Prodrug‐Based Approaches

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MA02.06 Phase 1b Study of Pelcitoclax (APG-1252) in Combination With Osimertinib in Patients With EGFR TKI-Resistant NSCLC

Cited by 5 publications

References 0 publications

Therapeutic potential of the novel Bcl‐2/Bcl‐XL dual inhibitor, APG1252, alone or in combination against non‐small cell lung cancer

Therapeutic potential of the novel Bcl‐2/Bcl‐XL dual inhibitor, APG1252, alone or in combination against non‐small cell lung cancer

Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-XL dual inhibitor that induces Bax-dependent apoptosis

Strategies to Reduce the On‐Target Platelet Toxicity of Bcl‐xL Inhibitors: PROTACs, SNIPERs and Prodrug‐Based Approaches

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Therapeutic potential of the novel Bcl‐2/Bcl‐X_L dual inhibitor, APG1252, alone or in combination against non‐small cell lung cancer

Therapeutic potential of the novel Bcl‐2/Bcl‐X_L dual inhibitor, APG1252, alone or in combination against non‐small cell lung cancer

Strategies to Reduce the On‐Target Platelet Toxicity of Bcl‐x_L Inhibitors: PROTACs, SNIPERs and Prodrug‐Based Approaches