Abstract A109: AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma.

Cross, Darren A.E.; Ashton, Sue; Nebhan, Caroline A.; Eberlein, Cath; Finlay, M. Raymond V.; Hughes, Adina; Jacobs, Vivien N.; Mellor, Martine J.; Brewer, Monica Red; Meador, Catherine B.; Orme, Jonathon P.; Spitzler, Paula J.; Powell, Steve; Rahi, Amar; Taylor, Paula; Ward, Richard A.; Daunt, Paula; Galer, Anne; Klinowska, Teresa; Richmond, Graham H.P.; Pao, William

doi:10.1158/1535-7163.targ-13-a109

Cited by 14 publications

(7 citation statements)

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“… 4 , 12 Other molecules in these two categories, including reversible and irreversible TKIs that inhibit the drug-resistant EGFR double mutant, are in clinical development. 13 − 19 Here we describe molecules that inhibit EGFR in a third way, via allostery, 20 , 21 by blocking the formation of a coiled coil dimer in the juxtamembrane (JM) segment (Figure 1 A) that is essential for assembly of the active, asymmetric kinase dimer.…”

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confidence: 99%

Inhibiting Epidermal Growth Factor Receptor at a Distance

2014

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The epidermal growth factor receptor (EGFR) tyrosine kinase is implicated in a large number of human cancers. Most EGFR inhibitors target the extracellular, growth factor-binding domain or the intracellular, ATP-binding domain. Here we describe molecules that inhibit the kinase activity of EGFR in a new way, by competing with formation of an essential intradimer coiled coil containing the juxtamembrane segment from each member of the receptor partnership. The most potent molecules we describe bind EGFR directly, decrease the proliferation of wild-type and mutant EGFR-dependent cells lines, inhibit phosphorylation of EGFR and downstream targets, and block coiled coil formation as judged by bipartite tetracysteine display. Potency is directly correlated with the ability to block coiled coil formation within full-length EGFR in cells.

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confidence: 99%

Inhibiting Epidermal Growth Factor Receptor at a Distance

2014

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“…OSIMERTINIB (AZD9291) was developed as a third-generation drug by AstraZeneca to treat patients with the T790M mutation resistant to generation I and II drugs [86,87]. Like afatinib, osimertinib is an irreversible inhibitor that covalently interacts with C797.…”

Section: Epidermal Growth Factor Receptor (Egfr)mentioning

confidence: 99%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

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Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

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“…AZD9291 is a potent, irreversible and effective inhibitor, both in sensitizing EGFR mutations and resistant mutations in cell lines in vitro , while sparing EGFR wild-type [ 71 ]. The drug demonstrated anti-tumor activity in EGFR -mutant xenografts at a low dose level [ 71 ]. A phase I open-label, multi-center trial has been performed with both Asian and Western patients with advanced NSCLC who had disease progression with prior EGFR-TKI therapy.…”

Section: Third-generation Egfr-tkismentioning

confidence: 99%

Re-Treatment with EGFR-TKIs in NSCLC Patients Who Developed Acquired Resistance

Chen

2014

JPM

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In the era of personalized medicine, epidermal growth factor receptor (EGFR) inhibition with tyrosine kinase inhibitor (TKI) has been a mainstay of treatment for non-small cell lung cancer (NSCLC) patients with an EGFR mutation. Acquired resistance, especially substitution of methionine for threonine at position 790 (T790M), which has accounted for more than half of the cases, developed inevitably in patients who were previously treated with EGFR-TKI. At present, there is no standard treatment for patients who have developed a resistance to EGFR-TKI. Several strategies have been developed or suggested to treat such patients. This article aimsto review the EGFR-TKI re-treatment strategy and the efficacy of different generations of EGFR-TKIs in patients with acquired resistance to prior EGFR-TKI.

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Abstract A109: AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma.

Cited by 14 publications

References 0 publications

Inhibiting Epidermal Growth Factor Receptor at a Distance

Inhibiting Epidermal Growth Factor Receptor at a Distance

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Re-Treatment with EGFR-TKIs in NSCLC Patients Who Developed Acquired Resistance

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