Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance

Maity, Swastika; Pai, K. Sreedhara Ranganath; Nayak, Yogendra

doi:10.1007/s43440-020-00131-0

Cited by 44 publications

(26 citation statements)

References 48 publications

(102 reference statements)

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“…Increasing clinical investigations have explored the value of fourth-generation EGFR TKIs plus antiangiogenic drugs as the first-line treatment for EGFR-mutated NSCLC. Fourth-generation EGFR TKIs should be reversible or allosteric mechanisms (Maity et al, 2020). Recent studies have proposed TPD, an alternative inhibition modality using small molecules.…”

Section: Summary and Future Prospectsmentioning

confidence: 99%

Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Duggirala

Lee

2022

Biomol Ther (Seoul)

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Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wildtype EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second-and thirdgeneration EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/ T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.

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Section: Summary and Future Prospectsmentioning

confidence: 99%

Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Duggirala

Lee

2022

Biomol Ther (Seoul)

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“…The combination of osimertinib with first-second generation EGFR TKIs in cases with C797X and T790M in trans could be effective as well as the use of first-second-generation EGFR TKIs in cases with C997X and the absence of the T790M mutation [68,104,117]. Preclinical models suggest the effectiveness of EGFR-TKI with cetuximab or brigatinib with anti-EGFR antibody, but clinical applications have yet to confirm them [89,[206][207][208].…”

Section: Egfr-dependent Mechanismsmentioning

confidence: 99%

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Reita

Pabst

Pencreach

et al. 2021

Cancers

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Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Activating epidermal growth factor receptor (EGFR) gene mutations are a positive predictive factor for EGFR tyrosine kinase inhibitors (TKIs). For common EGFR mutations (Del19, L858R), the standard first-line treatment is actually third-generation TKI, osimertinib. In the case of first-line treatment by first (erlotinib, gefitinib)- or second-generation (afatinib) TKIs, osimertinib is approved in second-line treatment for patients with T790M EGFR mutation. Despite the excellent disease control results with EGFR TKIs, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and possible drug targets, which vary among the generation/line of EGFR TKIs. Besides EGFR second/third mutations, alternative mechanisms could be involved, such as gene amplification or gene fusion, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of EGFR TKIs and should be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research.

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“…The complexity of the mechanisms associated with acquired EGFR-TKI resistance in NSCLC has been widely demonstrated ( 15 ), and can be grouped into kinase domain mutations and overexpression of target oncogenes within tumor cells ( 9 ). The EGFR T790M mutation is the primary cause of drug resistance in 50–60% of instances, while activating genomic alterations in other kinases, such as ALK, ROS1, MET, RET, NTRK, and BRAF, have been validated as targets in NSCLC therapy ( Figure 1 ) ( 16 ). It is evident that secondary (T790M) or tertiary (C797S) mutations are the main factors responsible for the development of acquired resistance ( 17 ).…”

Section: Different Mechanisms Of Chemotherapy Resistance In Nsclcmentioning

confidence: 99%

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer

Luo

et al. 2021

Front. Oncol.

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Resistance is the major cause of treatment failure and disease progression in non-small cell lung cancer (NSCLC). There is evidence that hypoxia is a key microenvironmental stress associated with resistance to cisplatin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and immunotherapy in solid NSCLCs. Numerous studies have contributed to delineating the mechanisms underlying drug resistance in NSCLC; nevertheless, the mechanisms involved in the resistance associated with hypoxia-induced molecular metabolic adaptations in the microenvironment of NSCLC remain unclear. Studies have highlighted the importance of posttranslational regulation of molecular mediators in the control of mitochondrial function in response to hypoxia-induced metabolic adaptations. Hypoxia can upregulate the expression of sirtuin 1 (SIRT1) in a hypoxia-inducible factor (HIF)-dependent manner. SIRT1 is a stress-dependent metabolic sensor that can deacetylate some key transcriptional factors in both metabolism dependent and independent metabolic pathways such as HIF-1α, peroxisome proliferator-activated receptor gamma (PPAR-γ), and PPAR-gamma coactivator 1-alpha (PGC-1α) to affect mitochondrial function and biogenesis, which has a role in hypoxia-induced chemoresistance in NSCLC. Moreover, SIRT1 and HIF-1α can regulate both innate and adaptive immune responses through metabolism-dependent and -independent ways. The objective of this review is to delineate a possible SIRT1/PGC-1α/PPAR-γ signaling-related molecular metabolic mechanism underlying hypoxia-induced chemotherapy resistance in the NSCLC microenvironment. Targeting hypoxia-related metabolic adaptation may be an attractive therapeutic strategy for overcoming chemoresistance in NSCLC.

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Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance

Cited by 44 publications

References 48 publications

Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer

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