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

Sjin, Robert Tjin Tham; Lee, Kwang-Ho; Walter, Annette O.; Dubrovskiy, Aleksandr; Sheets, Michael P.; Martin, Thomas N.; Labenski, Matthew; Zhu, Zhendong; Tester, Richland; Karp, Russell; Medikonda, Aravind; Chaturvedi, Prasoon; Ren, Yixuan; Haringsma, Henry J.; Etter, Jeff; Raponi, Mitch; Simmons, Andrew; Harding, Thomas C.; Niu, Deqiang; Nacht, Mariana; Westlin, William; Petter, Russell C.; Allen, Andrew R.; Singh, Juswinder

doi:10.1158/1535-7163.mct-13-0966

Cited by 60 publications

(39 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pharmacokinetic and pharmacodynamic studies in H1975 (EGFR L858R/T790M) tumor-bearing mice showed that exposure was dose proportional resulting in dose-dependent EGFR modulation. As indicated for AZD9291, this compound showed no inhibition of wild type EGFR in animals [63]. CO-1686 is currently in a phase I/II clinical trial in patients with EGFR mutated-advanced NSCLC that have received prior EGFR-directed therapy.…”

Section: T790m and Third Generation Tkimentioning

confidence: 99%

EGFR T790M resistance mutation in non small-cell lung carcinoma

Denis

Vallée

Théoleyre

2015

Clinica Chimica Acta

View full text Add to dashboard Cite

Section: T790m and Third Generation Tkimentioning

confidence: 99%

EGFR T790M resistance mutation in non small-cell lung carcinoma

Denis

Vallée

Théoleyre

2015

Clinica Chimica Acta

View full text Add to dashboard Cite

“…Here, we sought to extend these initial findings by determining the proteome-wide reactivity of third-generation inhibitors for EGFR designed to selectively and irreversibly target the T790M drug-resistant mutant form of this kinase. All three inhibitors investigated – the recently approved osimertinib (Tagrisso, AZD9291; 1 , Figure 1A), PF-06747775 ( 2 , Figure 1A) and rociletinib (CO-1686; 3 , Figure 1A) – were optimized for an EGFR inhibition profile that maintained good potency against the two original drug-sensitive, kinase-activating mutants (exon19Del and L858R) and the two major drug-resistant T790M mutants (exon19Del/T790M and L858R/T790M), while showing reduced activity against wild type (WT)-EGFR to minimize mechanism-based toxicity (Cross et al, 2014, Finlay et al, 2014, Tjin Tham Sjin et al, 2014, Walter et al, 2013, Planken et al, 2017). Our chemical proteomic studies reveal that, despite the highly engineered EGFR mutant inhibition profile achieved by all three third-generation inhibitors and their shared unsubstituted acrylamide reactive group, the inhibitors exhibited strikingly distinct proteome-wide reactivity profiles in human cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors

Niessen

Dix

Barbas

et al. 2017

Cell Chemical Biology

View full text Add to dashboard Cite

Summary Patients with non-small cell lung cancer (NSCLC) that have kinase-activating epidermal growth factor receptor (EGFR) mutations are highly responsive to first- and second-generation EGFR inhibitors. However, these patients often relapse due to a secondary, drug-resistant mutation in EGFR where the gatekeeper threonine is converted to methionine (T790M). Several third-generation EGFR inhibitors have been developed that irreversibly inactivate T790M-EGFR while sparing wild-type EGFR, thus reducing epithelium-based toxicities. Using chemical proteomics, we show here that individual T790M-EGFR inhibitors exhibit strikingly distinct off-target profiles in human cells. The FDA-approved drug osimertinib (AZD9291), in particular, was found to covalently modify cathepsins in cell and animal models, which correlated with lysosomal accumulation of the drug. Our findings thus show how chemical proteomics can be used to differentiate covalent kinase inhibitors based on global selectivity profiles in living systems and identify specific off-targets of these inhibitors that may impact drug activity and safety.

show abstract

“…The most common mechanism of resistance, accounting for 60% of cases, is the occurrence of the secondary mutation T790M (replacing a gatekeeper amino acid) in the EGFR allele harboring the TKI-sensitive mutation [5]. To overcome resistance to conventional EGFR-TKIs, a new generation of drugs (including AZD9291, CO-1686, and HM61713) that suppress the kinase activity of EGFR proteins harboring secondary T790M substitutions is currently being developed [6][7][8][9]. Phase I clinical trials demonstrate that progressed NSCLC patients who are diagnosed with T790M-positive tumors by genetic testing of rebiopsied tumor tissues respond to these new drugs [10].…”

Section: Introductionmentioning

confidence: 99%

Picoliter-Droplet Digital Polymerase Chain Reaction-Based Analysis of Cell-Free Plasma DNA to AssessEGFRMutations in Lung Adenocarcinoma That Confer Resistance to Tyrosine-Kinase Inhibitors

Seki

Fujiwara²,

Kohno³

et al. 2016

The Oncologist

View full text Add to dashboard Cite

Next-generation sequencing ABSTRACTPurpose. The objective of this study was to evaluate the utility of analyzing cell-free plasma DNA (cfDNA) by picoliter-droplet digital polymerase chain reaction (ddPCR) to detect EGFR mutations that confer resistance to tyrosine-kinase inhibitors (TKIs) used for treatment of lung adenocarcinoma (LADC). Experimental design. Thirty-five LADC patients who received epidermal growth factor receptor (EGFR)-TKI therapy, including ten who received tumor rebiopsy after development of resistance, were subjected to picoliter-ddPCR-cfDNA analysis to determine the fraction of cfDNA with TKI-sensitive (L858R and inflame exon 19 deletions) and -resistant (i.e., T790M) mutations, as well as their concordance with mutation status in rebiopsied tumor tissues. Results. cfDNA samples from 15 (94%) of 16 patients who acquired resistance were positive for TKI-sensitive mutations. Also, 7 (44%) were positive for the T790M mutation, with fractions of T790M (1) cfDNA ranging from 7.4% to 97%. T790M positivity in cfDNA was consistent in eight of ten patients for whom rebiopsied tumor tissues were analyzed, whereas the remaining cases were negative in cfDNA and positive in rebiopsied tumors. Prior to EGFR-TKI therapy, cfDNAs from 9 (38%) and 0 of 24 patients were positive for TKIsensitive and T790M mutations, respectively. Next-generation sequencing of cfDNA from one patient who exhibited innate resistance to TKI despite a high fraction of TKI-sensitive mutations and the absence of the T790M mutation in his cfDNA revealed the presence of the L747P mutation, a known driver of TKI resistance. Conclusion. Picoliter-ddPCR examination of cfDNA, supported by next-generation sequencing analysis, enables noninvasive assessment of EGFR mutations that confer resistance to TKIs. The Oncologist 2016;21:156-164 Implications for Practice: Noninvasive monitoring of the predominance of tumors harboring the secondary T790M mutation in the activating mutation in EGFR gene is necessary for precise and effective treatment of lung adenocarcinoma. Because cells harboring the T790M mutation are resistant to epidermal growth factor receptor-tyrosine-kinase inhibitors (TKIs), the predominance of tumor cells harboring the T790M mutations influences the choice of whether to use conventional or next-generation TKIs. Digital polymerase chain reaction-based examination of cfDNA is a promising method; however, its feasibility, including its consistency with examination of rebiopsied tumor tissue, has not been fully proven. Here, picoliter-droplet digital polymerase chain reaction technology is presented as a candidate method for testing cfDNA and assessing the predominance of T790M-mutant tumors.

show abstract

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

Cited by 60 publications

References 35 publications

EGFR T790M resistance mutation in non small-cell lung carcinoma

EGFR T790M resistance mutation in non small-cell lung carcinoma

Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors

Picoliter-Droplet Digital Polymerase Chain Reaction-Based Analysis of Cell-Free Plasma DNA to AssessEGFRMutations in Lung Adenocarcinoma That Confer Resistance to Tyrosine-Kinase Inhibitors

Contact Info

Product

Resources

About