Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC

Walter, Annette O.; Sjin, Robert Tjin Tham; Haringsma, Henry J.; Ohashi, Kadoaki; Sun, Jing; Lee, Kwang-Ho; Dubrovskiy, Aleksander; Labenski, Matthew; Zhu, Zhendong; Wang, Zhigang; Sheets, Michael P.; Martin, Thomas N.; Karp, Russell; Kalken, Dan van; Chaturvedi, Prasoon; Niu, Deqiang; Nacht, Mariana; Petter, Russell C.; Westlin, William; Lin, Kevin; Jaw-Tsai, Sarah; Raponi, Mitch; Dyke, Terry Van; Etter, Jeff; Weaver, Zoë; Pao, William; Singh, Juswinder; Simmons, Andrew; Harding, Thomas C.; Allen, Andrew R.

doi:10.1158/2159-8290.cd-13-0314

Cited by 563 publications

(524 citation statements)

References 44 publications

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“…Our results showed that among all compounds evaluated, compound 3 had the overall desired EGFR mutant selectivity profile and was selected as a development candidate. More recently, in a companion manuscript, Walter and colleagues further evaluated compound 3 in additional EGFR wild type and EGFR mutant cell lines, several xenograft tumor models, and induction of acquired resistance after prolonged exposure to compound 3 (26). The results are consistent and complementary to the data presented here supporting compound 3 as an EGFR mutant-selective drug.…”

Section: Introductionsupporting

confidence: 69%

In Vitro and In Vivo Characterization of Irreversible Mutant-Selective EGFR Inhibitors That Are Wild-Type Sparing

Sjin

Lee

Walter

et al. 2014

Molecular Cancer Therapeutics

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Patients with non-small cell lung carcinoma (NSCLC) with activating mutations in epidermal growth factor receptor (EGFR) initially respond well to the EGFR inhibitors erlotinib and gefitinib. However, all patients relapse because of the emergence of drug-resistant mutations, with T790M mutations accounting for approximately 60% of all resistance. Second-generation irreversible EGFR inhibitors are effective against T790M mutations in vitro, but retain affinity for wild-type EGFR (EGFR WT

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Section: Introductionsupporting

confidence: 69%

In Vitro and In Vivo Characterization of Irreversible Mutant-Selective EGFR Inhibitors That Are Wild-Type Sparing

Sjin

Lee

Walter

et al. 2014

Molecular Cancer Therapeutics

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“…Rociletinib is EGFR-mutant-selective; it targets commonly monitored EGFR mutations, particularly T790M, and spares the WT-EGFR at the same time [33]. As part of a phase I/II study (TIGER-X), researchers carried out a dosage determination trial for 130 EGFR-mutant NSCLC patients who acquired resistance after EGFR-TKI treatment.…”

Section: Rociletinib (Co-1686) Is Another Third-generation Egfr-tkimentioning

confidence: 99%

“…Rociletinib also exhibits a reasonable toxicity profile with hyperglycemia (47% for all grades), nausea (35%), and fatigue (24%) as the most prevalent side effects (Table 3) [34]. The hyperglycemic side effect is suggested to be primarily associated with the metabolite M502, which causes hyperglycemia by blocking the insulin growth factor type-1 receptor and insulin receptor [33]. Rociletinib has also been demonstrated to be effective on CNS metastases.…”

Section: Rociletinib (Co-1686) Is Another Third-generation Egfr-tkimentioning

confidence: 99%

Treatment After First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non- Small-Cell Lung Cancer

Kazaz

Öztop

2017

Turk Thorac J

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Systemic treatment is the basic treatment approach to advanced-stage non-small-cell lung cancer (NSCLC), and chemotherapy and targeted treatments are commonly employed in these patients. Recently, positive results achieved with immunotherapy have led to a growing number of treatment options and prolonged survival time. Today, specific tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and the TKI crizotinib, which targets anaplastic lymphoma kinase gene rearrangement, have become the standard treatment among targeted therapies for patients with sensitive molecular anomalies. However, resistance develops against all these agents after a while. Numerous genetic mutations, T790M+ in particular, have been identified as resistance mechanisms against EGFR-TKIs, and researchers are developing specific inhibitors against them. Among those inhibitors, third-generation EGFR-TKIs such as osimertinib and rociletinib have gained prominence due to their high level of effectiveness and low toxicity profile. Besides, systemic chemotherapy and immunotherapy are proper alternatives. A second biopsy during the progression stage and better clarification of the mechanisms causing secondary resistance will enable more successful treatments in the future. KEYWORDS:Epidermal growth factor receptor, tyrosine kinase inhibitors, resistance, non-small-cell lung cancer INTRODUCTIONLung cancer is still the primary cause of cancer-related death for both sexes worldwide, causing approximately 1.4 million deaths every year [1]. Non-small-cell lung cancer (NSCLC) cases comprise approximately 80%-85% of all lung cancers. More than half of the NSCLC cases are advanced-stage at the time of diagnosis, and those patients are characterized by poor prognosis. Systemic chemotherapy has long been employed as the primary treatment approach for advanced-stage NSCLC. Despite a series of advances in chemotherapy and the application of histology-based approaches in the course of time, median survival time does not exceed 1 year [2]. On the other hand, recent discoveries of somatic mutations in NSCLC and the employment of specific inhibitors against them have led to significant changes in the treatment of advanced-stage NSCLC. Currently, there are two key oncogenic molecular anomalies reflected in routine practice: epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase gene rearrangement.Epidermal growth factor receptor mutations are observed in approximately 10% of the whole patient group, whereas this rate may go up to 40% among Asians, non-smokers, and in patients who have adenocarcinoma histology. Deletion at exon 19 and point mutation at exon 21 (L858R) are the most common EGFR mutations [3]. The presence of these mutations indicates sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. The use of erlotinib and gefitinib (first-generation TKIs) and afatinib (second-generation TKIs) in first-, second-, a...

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“…Second generation TKIs (Afatinib, Dacomitinib) differ from first generation EGFR-TKIs because they form an irreversible link to the EGFR kinase domain and inhibit receptors as HER2 and HER4 and are active agents particularly in those with exon 19 deletion. The increasing knowledge in tumor biology and the mechanisms, by which resistance develops, have helped to develop new molecules that have already demonstrated a positive impact on response rates and survival [9][10][11].…”

Section: First and Second Generation Of Egfr Inhibitorsmentioning

confidence: 99%

“…Rociletinib, is a new oral selective covalent molecule EGFR inhibitor, with demonstrated activity against the T790M mutation, deletionn 19 and L858R [19][20]. Initial studies were performed in patients with acquired resistance to gefitinib and erlotinib.…”

Section: Rociletinib (Co-16086)mentioning

confidence: 99%

Tyrosine kinase inhibitors: new molecules in non-small cell lung cancer (EGFR AND ALK)

et al. 2017

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Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC

Cited by 563 publications

References 44 publications

In Vitro and In Vivo Characterization of Irreversible Mutant-Selective EGFR Inhibitors That Are Wild-Type Sparing

In Vitro and In Vivo Characterization of Irreversible Mutant-Selective EGFR Inhibitors That Are Wild-Type Sparing

Treatment After First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non- Small-Cell Lung Cancer

Tyrosine kinase inhibitors: new molecules in non-small cell lung cancer (EGFR AND ALK)

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