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Updated: Nov 15, 2025
Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Upfront admixing antibodies and EGFR inhibitors preempts sequential treatments in lung cancer models
Ilaria Marrocco1, Donatella Romaniello1, Itay Vaknin1
1Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
Some antibacterial therapies entail sequential treatments with different antibiotics, but whether this approach is optimal for anti-cancer tyrosine kinase inhibitors (TKIs) remains open. EGFR mutations identify lung cancer patients who can derive benefit from TKIs, but most patients develop resistance to the first-, second-, and third-generation drugs. To explore alternatives to such whack-a-mole strategies, we simulated in patient-derived xenograft models the situation of patients receiving first-line TKIs. Monotherapies comprising approved first-line TKIs were compared to combinations with antibodies specific to EGFR and HER2. We observed uniform and strong superiority of all drug combinations over the respective monotherapies. Prolonged treatments, high TKI dose, and specificity were essential for drug-drug cooperation. Blocking pathways essential for mitosis (e.g., FOXM1), along with downregulation of resistance-conferring receptors (e.g., AXL), might underlie drug cooperation. Thus, upfront treatments using combinations of TKIs and antibodies can prevent emergence of resistance and hence might replace the widely applied sequential treatments utilizing next-generation TKIs.
Insights
Combining tyrosine kinase inhibitors (TKIs) with antibodies upfront, rather than sequential treatments, significantly improves lung cancer therapy. This combination approach prevents drug resistance, offering a superior alternative to current sequential TKI strategies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Sequential antibiotic therapy is common, but its efficacy for anti-cancer tyrosine kinase inhibitors (TKIs) is uncertain.
- Most lung cancer patients with EGFR mutations develop resistance to sequential generations of TKIs.
- Current 'whack-a-mole' strategies using next-generation TKIs are suboptimal for overcoming resistance.
Purpose of the Study:
- To evaluate upfront combination therapy versus sequential monotherapy for lung cancer.
- To explore alternatives to sequential treatment strategies for tyrosine kinase inhibitors (TKIs).
- To investigate the optimal use of TKIs in combination with antibodies targeting EGFR and HER2.
Main Methods:
- Patient-derived xenograft models were used to simulate first-line TKI treatment scenarios.
- Monotherapies with approved first-line TKIs were compared against combinations with EGFR- and HER2-specific antibodies.
- Key factors for drug cooperation, such as treatment duration, TKI dose, and specificity, were analyzed.
Main Results:
- All drug combinations demonstrated uniform and significant superiority over respective monotherapies.
- Prolonged treatment, high TKI dosage, and specificity were crucial for achieving drug-drug cooperation.
- Underlying mechanisms may involve blocking mitotic pathways (e.g., FOXM1) and downregulating resistance receptors (e.g., AXL).
Conclusions:
- Upfront combination therapy with TKIs and antibodies is superior to sequential TKI treatments.
- This combination strategy can prevent the emergence of drug resistance in lung cancer.
- Combination therapy may replace sequential treatments with next-generation TKIs, improving patient outcomes.
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