Management of diarrhea induced by EGFR-TKIs in advanced lung adenocarcinoma

Cárdenas-Fernández, Daniela; Soberanis Pina, Pamela; Turcott, Jenny G.; Chávez-Tapia, Norberto; Conde-Flores, Emilio; Cardona, Andrés F.; Arrieta, Oscar

doi:10.1177/17588359231192396

Cited by 3 publications

(1 citation statement)

References 107 publications

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“…Once the side effects are resolved, the original dose is often restored. Compared with chemotherapy regimens, first-generation regimens have shown a much better side-effect profile and fewer serious (grade 3–4) adverse events [ 13 , 15 – 18 ].…”

Section: First-generation Reversible Egfr Inhibitorsmentioning

confidence: 99%

Targeted therapeutic options in early and metastatic NSCLC-overview

Gálffy,

Morócz,

Korompay

et al. 2024

Pathol. Oncol. Res.

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The complex therapeutic strategy of non-small cell lung cancer (NSCLC) has changed significantly in recent years. Disease-free survival increased significantly with immunotherapy and chemotherapy registered in perioperative treatments, as well as adjuvant registered immunotherapy and targeted therapy (osimertinib) in case of EGFR mutation. In oncogenic-addictive metastatic NSCLC, primarily in adenocarcinoma, the range of targeted therapies is expanding, with which the expected overall survival increases significantly, measured in years. By 2021, the FDA and EMA have approved targeted agents to inhibit EGFR activating mutations, T790 M resistance mutation, BRAF V600E mutation, ALK, ROS1, NTRK and RET fusion. In 2022, the range of authorized target therapies was expanded. With therapies that inhibit KRASG12C, EGFR exon 20, HER2 and MET. Until now, there was no registered targeted therapy for the KRAS mutations, which affect 30% of adenocarcinomas. Thus, the greatest expectation surrounded the inhibition of the KRAS G12C mutation, which occurs in ∼15% of NSCLC, mainly in smokers and is characterized by a poor prognosis. Sotorasib and adagrasib are approved as second-line agents after at least one prior course of chemotherapy and/or immunotherapy. Adagrasib in first-line combination with pembrolizumab immunotherapy proved more beneficial, especially in patients with high expression of PD-L1. In EGFR exon 20 insertion mutation of lung adenocarcinoma, amivantanab was registered for progression after platinum-based chemotherapy. Lung adenocarcinoma carries an EGFR exon 20, HER2 insertion mutation in 2%, for which the first targeted therapy is trastuzumab deruxtecan, in patients already treated with platinum-based chemotherapy. Two orally administered selective c-MET inhibitors, capmatinib and tepotinib, were also approved after chemotherapy in adenocarcinoma carrying MET exon 14 skipping mutations of about 3%. Incorporating reflex testing with next-generation sequencing (NGS) expands personalized therapies by identifying guideline-recommended molecular alterations.

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Section: First-generation Reversible Egfr Inhibitorsmentioning

confidence: 99%

Targeted therapeutic options in early and metastatic NSCLC-overview

Gálffy,

Morócz,

Korompay

et al. 2024

Pathol. Oncol. Res.

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The effect of food on the pharmacokinetics of Sutetinib maleate capsule, an irreversible EGFR tyrosine kinase inhibitor, in healthy Chinese subjects

Cao,

Ma,

Zhang

et al. 2024

Invest New Drugs

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Discovery of 1H-benzo[d]imidazole-(halogenated) Benzylidenebenzohydrazide Hybrids as Potential Multi-Kinase Inhibitors

Mirgany,

Asiri,

Rahman

et al. 2024

Pharmaceuticals

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In an effort to develop improved and effective targeted tyrosine kinase inhibitors (TKIs), a series of twelve novel compounds with the structural motif “(E)-4-(((1H-benzo[d]imidazol-2-yl)methyl)amino)-N′-(halogenated)benzylidenebenzohydrazide” were successfully synthesized in three steps, yielding high product yields (53–97%). Among this new class of compounds, 6c and 6h-j exhibited excellent cytotoxic effects against four different cancer cell lines, with half-maximal inhibitory concentration (IC50) values ranging from 7.82 to 21.48 μM. Notably, compounds 6h and 6i emerged as the most potent inhibitors, demonstrating significant activity against key kinases such as EGFR, HER2, and CDK2. Furthermore, compound 6h displayed potent inhibitory activity against AURKC, while 6i showed potent inhibitory effects against the mTOR enzyme, with excellent IC50 values comparable with well-established TKIs. The mechanistic study of lead compound 6i revealed its ability to induce cell cycle arrest and apoptosis in HepG2 liver cancer cells. This was accompanied by upregulation of pro-apoptotic caspase-3 and Bax and downregulation of anti-apoptotic Bcl-2. Additionally, molecular docking studies indicated that the binding interactions of compounds 6h and 6i with the target enzymes give multiple interactions. These results underscore the ability of compound 6i as a compelling lead candidate warranting further optimization and development as a potent multi-targeted kinase inhibitor, which could have significant implications for the treatment of various cancers. The detailed structural optimization, mechanism of action, and in vivo evaluation of this class of compounds warrant further investigation to assess their therapeutic potential.

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Management of diarrhea induced by EGFR-TKIs in advanced lung adenocarcinoma

Cited by 3 publications

References 107 publications

Targeted therapeutic options in early and metastatic NSCLC-overview

Targeted therapeutic options in early and metastatic NSCLC-overview

The effect of food on the pharmacokinetics of Sutetinib maleate capsule, an irreversible EGFR tyrosine kinase inhibitor, in healthy Chinese subjects

Discovery of 1H-benzo[d]imidazole-(halogenated) Benzylidenebenzohydrazide Hybrids as Potential Multi-Kinase Inhibitors

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