L858R emerges as a potential biomarker predicting response of lung cancer models to anti-EGFR antibodies: Comparison of osimertinib vs. cetuximab

Marrocco, Ilaria; Giri, Suvendu; Simoni‐Nieves, Arturo; Gupta, Nitin; Rudnitsky, Anna; Haga, Yuya; Romaniello, Donatella; Sekar, Arunachalam; Zerbib, Mirie; Oren, Roni; Lindzen, Moshit; Fard, Damon; Tsutsumi, Yasuo; Lauriola, Mattia; Tamagnone, Luca; Yarden, Yosef

doi:10.1016/j.xcrm.2023.101142

Cited by 3 publications

(1 citation statement)

References 60 publications

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“…Beyond NSCLC, instances of EGFR mutations, including L858R, have been detected in select cases of head and neck squamous cell carcinoma ( Stransky et al, 2011 ). The emergence of L858R as a potential biomarker holds promise for predicting the responsiveness of lung cancer models to anti-EGFR therapy ( Marrocco et al, 2023 ). Notably, the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has demonstrated considerable efficacy in NSCLC patients harboring this mutation, offering a favorable side effect profile and contributing to an improved quality of life ( Mitani et al, 2020 ).…”

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confidence: 99%

Computational insights into the stereo-selectivity of catechins for the inhibition of the cancer therapeutic target EGFR kinase

Rehan,

Ahmed,

Khan

et al. 2024

Front. Pharmacol.

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The epidermal growth factor receptor (EGFR) plays a crucial role in regulating cellular growth and survival, and its dysregulation is implicated in various cancers, making it a prime target for cancer therapy. Natural compounds known as catechins have garnered attention as promising anticancer agents. These compounds exert their anticancer effects through diverse mechanisms, primarily by inhibiting receptor tyrosine kinases (RTKs), a protein family that includes the notable member EGFR. Catechins, characterized by two chiral centers and stereoisomerism, demonstrate variations in chemical and physical properties due to differences in the spatial orientation of atoms. Although previous studies have explored the membrane fluidity effects and transport across cellular membranes, the stereo-selectivity of catechins concerning EGFR kinase inhibition remains unexplored. In this study, we investigated the stereo-selectivity of catechins in inhibiting EGFR kinase, both in its wild-type and in the prevalent L858R mutant. Computational analyses indicated that all stereoisomers, including the extensively studied catechin (−)-EGCG, effectively bound within the ATP-binding site, potentially inhibiting EGFR kinase activity. Notably, gallated catechins emerged as superior EGFR inhibitors to their non-gallated counterparts, revealing intriguing binding trends. The top four stereoisomers exhibiting high dock scores and binding energies with wild-type EGFR comprise (−)-CG (−)-GCG (+)-CG, and (−)-EGCG. To assess dynamic behavior and stability, molecular dynamics simulations over 100 ns were conducted for the top-ranked catechin (−)-CG and the widely investigated catechin (−)-EGCG with EGFR kinase. This study enhances our understanding of how the stereoisomeric nature of a drug influences inhibitory potential, providing insights that could guide the selection of specific stereoisomers for improved efficacy inexisting drugs.

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Section: Introductionmentioning

confidence: 99%

Computational insights into the stereo-selectivity of catechins for the inhibition of the cancer therapeutic target EGFR kinase

Rehan,

Ahmed,

Khan

et al. 2024

Front. Pharmacol.

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Resistance of Lung Cancer to EGFR-Specific Kinase Inhibitors: Activation of Bypass Pathways and Endogenous Mutators

Marrocco,

Yarden

2023

Cancers

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Epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) have changed the landscape of lung cancer therapy. For patients who are treated with the new TKIs, the current median survival exceeds 3 years, substantially better than the average 20 month survival rate only a decade ago. Unfortunately, despite initial efficacy, nearly all treated patients evolve drug resistance due to the emergence of either new mutations or rewired signaling pathways that engage other receptor tyrosine kinases (RTKs), such as MET, HER3 and AXL. Apparently, the emergence of mutations is preceded by a phase of epigenetic alterations that finely regulate the cell cycle, bias a mesenchymal phenotype and activate antioxidants. Concomitantly, cells that evade TKI-induced apoptosis (i.e., drug-tolerant persister cells) activate an intrinsic mutagenic program reminiscent of the SOS system deployed when bacteria are exposed to antibiotics. This mammalian system imbalances the purine-to-pyrimidine ratio, inhibits DNA repair and boosts expression of mutation-prone DNA polymerases. Thus, the net outcome of the SOS response is a greater probability to evolve new mutations. Deeper understanding of the persister-to-resister transformation, along with the development of next-generation TKIs, EGFR-specific proteolysis targeting chimeras (PROTACs), as well as bispecific antibodies, will permit delaying the onset of relapses and prolonging survival of patients with EGFR+ lung cancer.

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Prognostic Factors and Markers in Non-Small Cell Lung Cancer: Recent Progress and Future Challenges

Meira,

de Castro e Caetano,

Casotti

et al. 2023

Genes

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Lung cancer is a highly aggressive neoplasm and, despite the development of recent therapies, tumor progression and recurrence following the initial response remains unsolved. Several questions remain unanswered about non-small cell lung cancer (NSCLC): (1) Which patients will actually benefit from therapy? (2) What are the predictive factors of response to MAbs and TKIs? (3) What are the best combination strategies with conventional treatments or new antineoplastic drugs? To answer these questions, an integrative literature review was carried out, searching articles in PUBMED, NCBI-PMC, Google Academic, and others. Here, we will examine the molecular genetics of lung cancer, emphasizing NSCLC, and delineate the primary categories of inhibitors based on their molecular targets, alongside the main treatment alternatives depending on the type of acquired resistance. We highlighted new therapies based on epigenetic information and a single-cell approach as a potential source of new biomarkers. The current and future of NSCLC management hinges upon genotyping correct prognostic markers, as well as on the evolution of precision medicine, which guarantees a tailored drug combination with precise targeting.

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L858R emerges as a potential biomarker predicting response of lung cancer models to anti-EGFR antibodies: Comparison of osimertinib vs. cetuximab

Cited by 3 publications

References 60 publications

Computational insights into the stereo-selectivity of catechins for the inhibition of the cancer therapeutic target EGFR kinase

Computational insights into the stereo-selectivity of catechins for the inhibition of the cancer therapeutic target EGFR kinase

Resistance of Lung Cancer to EGFR-Specific Kinase Inhibitors: Activation of Bypass Pathways and Endogenous Mutators

Prognostic Factors and Markers in Non-Small Cell Lung Cancer: Recent Progress and Future Challenges

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