Related Experiment Video
Updated: Dec 14, 2025
Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
Mechanisms of osimertinib resistance and emerging treatment options
Sabine Schmid1, Janice J N Li2, Natasha B Leighl2
1University Health Network, Princess Margret Cancer Centre, Toronto, Canada; Cantonal Hospital St. Gallen, Department of Oncology and Hematology, St.Gallen, Switzerland.
Abstract:
Osimertinib is an irreversible EGFR-tyrosine kinase inhibitor initially approved for treatment of EGFR-positive patients exhibiting a T790 M resistance mutation in the second line setting and now emerging as the new standard of care for all EGFR positive patients as first-line treatment. Despite its efficacy, resistance to osimertinib inevitably develops and mechanisms of resistance can be grouped broadly in two categories: on-target EGFR-dependent and off-target EGFR-independent mechanisms. EGFR-dependent resistance typically is associated with additional EGFR-mutations disrupting the osimertinib binding through changes in the binding site by allosteric/ conformational transitions; EGFR-independent mechanisms are related mostly to alternate pathway activation or aberrant downstream signalling but also to lineage plasticity leading to small cell transformation. MET amplification is the most frequent off-target mechanisms of resistance to osimertinib treatment and recently published early trials show promising results for combination of MET-inhibitors with osimertinib upon development of resistance. This review will summarize mechanisms of resistance overall and in different treatment settings and will focus on potential new treatment options targeting specific acquired alterations after osimertinib failure.
Insights
Osimertinib resistance in EGFR-positive cancers arises from on-target mutations or off-target pathways like MET amplification. New combination therapies targeting these resistance mechanisms show promise for improved patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Osimertinib, an irreversible EGFR-tyrosine kinase inhibitor, is a standard treatment for EGFR-positive lung cancer.
- Resistance to osimertinib inevitably develops, necessitating an understanding of its mechanisms.
- Mechanisms of resistance are broadly categorized into EGFR-dependent and EGFR-independent pathways.
Purpose of the Study:
- To review the mechanisms of osimertinib resistance in EGFR-positive cancers.
- To explore emerging treatment strategies targeting acquired resistance alterations.
- To provide insights into overcoming treatment failure in EGFR-mutated lung cancer.
Main Methods:
- Literature review of studies on osimertinib resistance mechanisms.
- Analysis of EGFR-dependent and EGFR-independent resistance pathways.
- Evaluation of clinical trial data for combination therapies.
Main Results:
- EGFR-dependent resistance involves secondary EGFR mutations or allosteric changes.
- EGFR-independent resistance includes alternate pathway activation, downstream signaling, and lineage plasticity (e.g., small cell transformation).
- MET amplification is a frequent off-target resistance mechanism, with MET-inhibitor combinations showing promise.
Conclusions:
- Understanding diverse resistance mechanisms is crucial for effective osimertinib treatment.
- Targeting specific acquired alterations, such as MET amplification, offers new therapeutic avenues.
- Combination strategies combining osimertinib with other agents are emerging as a promising approach to overcome resistance.
More Related Videos
09:38Establishing 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
08:46Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Related Concept Videos
02:56Treatment Resistant Cancers
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
01:26Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...