Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models
Abstract Background Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against onc...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-07-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-022-09799-4 |
| _version_ | 1818198368686440448 |
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| author | Douglas D. Fang Ran Tao Guangfeng Wang Yuanbao Li Kaixiang Zhang Chunhua Xu Guoqin Zhai Qixin Wang Jingwen Wang Chunyang Tang Ping Min Dengkun Xiong Jianyong Chen Shaomeng Wang Dajun Yang Yifan Zhai |
| author_facet | Douglas D. Fang Ran Tao Guangfeng Wang Yuanbao Li Kaixiang Zhang Chunhua Xu Guoqin Zhai Qixin Wang Jingwen Wang Chunyang Tang Ping Min Dengkun Xiong Jianyong Chen Shaomeng Wang Dajun Yang Yifan Zhai |
| author_sort | Douglas D. Fang |
| collection | DOAJ |
| description | Abstract Background Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations. Methods KINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic–pharmacodynamic correlations and the mechanism of actions driving drug combination synergy. Results In mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449. Conclusions Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK + NSCLC refractory to earlier-generation ALK inhibitors. Trial registration Clinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019). |
| first_indexed | 2024-12-12T02:04:46Z |
| format | Article |
| id | doaj.art-1dd21e343843436b9e179e454cd45d0c |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-12T02:04:46Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-1dd21e343843436b9e179e454cd45d0c2022-12-22T00:42:05ZengBMCBMC Cancer1471-24072022-07-0122111510.1186/s12885-022-09799-4Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer modelsDouglas D. Fang0Ran Tao1Guangfeng Wang2Yuanbao Li3Kaixiang Zhang4Chunhua Xu5Guoqin Zhai6Qixin Wang7Jingwen Wang8Chunyang Tang9Ping Min10Dengkun Xiong11Jianyong Chen12Shaomeng Wang13Dajun Yang14Yifan Zhai15Ascentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdPharmacology and Medicinal Chemistry, Michigan Center for Therapeutic Innovation, University of MichiganAscentage Pharma (Suzhou) Co., LtdAscentage Pharma (Suzhou) Co., LtdAbstract Background Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations. Methods KINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic–pharmacodynamic correlations and the mechanism of actions driving drug combination synergy. Results In mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449. Conclusions Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK + NSCLC refractory to earlier-generation ALK inhibitors. Trial registration Clinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019).https://doi.org/10.1186/s12885-022-09799-4Anaplastic lymphoma kinase (ALK)Focal adhesion kinase (FAK)ROS proto-oncogene 1 receptor tyrosine kinase (ROS1)Solid tumorsTargeted therapies |
| spellingShingle | Douglas D. Fang Ran Tao Guangfeng Wang Yuanbao Li Kaixiang Zhang Chunhua Xu Guoqin Zhai Qixin Wang Jingwen Wang Chunyang Tang Ping Min Dengkun Xiong Jianyong Chen Shaomeng Wang Dajun Yang Yifan Zhai Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models BMC Cancer Anaplastic lymphoma kinase (ALK) Focal adhesion kinase (FAK) ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) Solid tumors Targeted therapies |
| title | Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models |
| title_full | Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models |
| title_fullStr | Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models |
| title_full_unstemmed | Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models |
| title_short | Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models |
| title_sort | discovery of a novel alk ros1 fak inhibitor apg 2449 in preclinical non small cell lung cancer and ovarian cancer models |
| topic | Anaplastic lymphoma kinase (ALK) Focal adhesion kinase (FAK) ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) Solid tumors Targeted therapies |
| url | https://doi.org/10.1186/s12885-022-09799-4 |
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