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Mechanisms of Acquired Resistance and Tolerance to EGFR Targeted Therapy in Non-Small Cell Lung Cancer (2024)

FAQs

What are the mechanisms of resistance to EGFR targeted therapies? ›

The most common mechanism of acquired resistance to first generation, reversible EGFR-TKIs is the emergence of the T790M gatekeeper mutation in the ATP binding pocket of EGFR, occurring in 50–60% of the patients that relapse after an initial response to gefitinib or erlotinib [27,28].

What are the mechanisms of resistance in NSCLC? ›

In the context of NSCLC, immunotherapeutic resistance can occur through several mechanisms (16–20): 1. Loss or downregulation of immune cell recognition; 2. Tumor microenvironment changes; 3. Immune checkpoint activation; 4.

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What is the most common mechanism of EGFR TKI resistance? ›

The most common mechanism is the development of acquired EGFR T790M mutation [9]. T790M was found in about 50% of EGFR–mutant cases that acquired resistance to EGFR TKIs [9]. Patients using either first- or second-generation EGFR TKIs had a similar prevalence of acquired T790M [10].

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What is the mechanism of action of EGFR mutation? ›

The initiation of epidermal growth factor receptor (EGFR) kinase activity proceeds via an asymmetric dimerization mechanism in which a “donor” tyrosine kinase domain (TKD) contacts an “acceptor” TKD, leading to its activation.

What is EGFR targeted therapy mechanism? ›

It reversibly binds to the adenosine triphosphate (ATP)-binding site of EGFR and completely inhibits autophosphorylation by EGFR tyrosine kinase. This results in blockage of downstream EGFR signal-transduction pathways, cell-cycle arrest, and inhibition of angiogenesis.

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What is a common mechanism in which patients undergoing targeted therapy with EGFR inhibitors develop resistance to these drugs? ›

The most common mechanism of resistance to first-generation EGFR tyrosine kinase inhibitors (e.g., gefitinib and erlotinib) is a mutation in the “gatekeeper” residue (the ATP binding site on the kinase), where methionine replaces threonine (T790M).

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What are the 4 mechanisms of resistance? ›

The main mechanisms of resistance are: limiting uptake of a drug, modification of a drug target, inactivation of a drug, and active efflux of a drug. These mechanisms may be native to the microorganisms, or acquired from other microorganisms.

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What are the acquired mechanisms of resistance? ›

The strategies that bacteria use to develop acquired resistance are encoded on plasmids and may be classified into four mechanisms: 1) decreased permeability of the cell wall to antibiotics; 2) modification of enzymes to inactivate antibiotics; 3) drug target site changes; and 4) efflux pumps that remove antibiotics ...

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What is the mechanism of action of nintedanib NSCLC? ›

The mechanism of action is thought to involve the restriction of neoangiogenesis by inhibiting various growth factors such as fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), colony-stimulating factor-1-receptor (CSF1R), and ...

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What is the mechanism of action of TKI therapy? ›

They work by blocking tyrosine kinase enzymes. TKI enzymes help manage how cells work, including cell signaling and growth and how often cells divide. Some tyrosine kinase inhibitors are used to treat cancer. TKIs work by blocking enzymes and keeping cancer cells from growing.

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What is resistance to TKI in Nsclc? ›

The advent of EGFR TKIs has been a game-changer for NSCLC treatments. However, resistance remains a significant challenge, particularly due to the upregulation of HER3. Combining HER3 targeting with EGFR TKIs emerges as a potent countermeasure against such resistance.

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What is the EGFR pathway mechanism? ›

EGFR Signaling Pathway Background

They have at least one common structural motif, the EGF domain, which consists of six conserved cysteine residues forming three disulfide bonds. The main structure of EGF domain is a two-stranded beta-sheet followed by a loop to a C-terminal short two-stranded sheet.

What are the most frequent EGFR mutations? ›

EGFR mutations occur in several hotspots between exons 18 and 21. In-frame deletion of exon 19 and L858R point mutation in exon 21 are the most common types of mutations detected, and account for 50% and 40% of patients' samples, respectively [8].

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What is the prognosis for EGFR mutation? ›

In patients with advanced non-small cell lung cancer (NSCLC), the presence of a common epidermal growth factor receptor (EGFR) mutation is prognostically favorable as these patients have a superior overall survival (OS) compared with patients with wild type EGFR status.

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What type of cancers are caused by EGFR mutation? ›

EGFR-positive lung cancer represents about 10-15% of lung cancer in the United States and generally appears in adenocarcinoma subtype of non-small cell lung cancer. Patients with lung cancers with EGFR mutations tend to have minimal to no smoking history.

What are the mechanisms of BRAF inhibitor resistance? ›

Multiple mechanisms of acquired resistance have been described, including elevated expression of the kinases CRAF, COT1, or mutant BRAF (8–11), activating mutations in N-RAS, MEK1, or AKT1 (12–14), aberrant splicing of BRAF (15), activation of phosphatidylinositol-3-OH kinase (PI3K) via the loss of PTEN (16), and ...

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What are the 4 major mechanisms of antimicrobial resistance please select? ›

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What are the mechanisms of CDK4 6 inhibitor resistance? ›

Resistance to CDK4/6 inhibitors can also occur through an acquired (extrinsic) mechanism. These mechanisms include over-activation of oncogenic signaling pathways, such as PI3K, MAPK, and TGFR signaling. PI3K mutation can also lead to overactivation of its signaling cascade.

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What are the mechanisms of resistance to PARP inhibitors? ›

The mechanisms of PARPi resistance are complex and mainly have the following ways: (i) the increase of drug efflux; (ii) genomic reversal of BRCA1/2; (iii) restoration of replication fork protection; (iv) any strengthening of the hom*ologous recombination repair process; (v) epigenetic modifications; and (vi) other ...