The highlight of resistance mechanism of targeted therapy on clinical therapy Zuhua Chen Dep. of GI...
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The highlight of resistance mechanism of targeted therapy on clinical therapy
Zuhua ChenDep. of GI oncology
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Targeted TherapyDrugs block the growth and spread of cancer by interfering with specific
molecules that are involved in the growth, progression, and spread of cancer.
Resistance
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The explore of resistance mechanisms to targeted therapy
• Patients with KRAS wild-type colorectal cancer
• KRAS exon 2 mutations predict a lack of response
• Not recommended in patients after progressing on EGFR
inhibitor
Nat Med. 2015; 21(7): 795–801.
Nature medicineClonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients
What’s the mechanism of efficacy of rechallenge therapies based on EGFR blockade?
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Detection of KRAS mutations in mCRC patients
Mutated KRAS emerge during anti-EGFR, decline upon withdrawal of anti-EGFR
Nat Med. 2015; 21(7): 795–801.
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Re-challenge with anti-EGFR in CRC cells and patients
Upon antibody withdrawal•KRAS clones decay •Drug sensitivity recover
Nat Med. 2015; 21(7): 795–801.
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Mutanted KRAS clones dynamically evolve in pulsatile therapy
Patients benefit from multiple challenges with anti-EGFR exhibit pulsatile levels of mutant KRAS
Nat Med. 2015; 21(7): 795–801.
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Highlights
Summary:•Clone evolution continues beyond clinical progression.•CRC genome adapts dynamically to intermittent drug schedules.
Clinical Significant:•Provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade.
Deficiency:•Single gene clone evolution VS multiple gene clone evolution.
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The explore of resistance mechanisms to targeted therapy
• AZD9291 is an irreversible, mutant-selective EGFR TKI
• EGFR activating mutations + T790M mutation
• ORR 61% , median PFS 9.6M
Nat Med. 2015; 21(7): 795–801.
Nature medicineAcquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M
What’s the mechanism of resistance to AZD9291 in NSCLC harboring EGFR T790M?
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The acquired EGFR C797S mutation in vitro
EGFR C797S mutation could be a mediator of acquired resistance to AZD9291
Nat Med. 2015; 21(7): 795–801.
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AZD9291 resistance related molecular subtypes
T790M(+)C797S(+) T790M(+)C797S(-) T790M(-)C797S(-)
Nat Med. 2015; 21(7): 795–801.
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The heterogeneity of C797S mutation
• T790M and C797S could exist on the same alleles or different alleles
• Does C797S locate in cis/trans with T790M alter drug sensitivity?
Nat Med. 2015; 21(7): 795–801.
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Allelic context of the C797Sm impacts sensitivity to treatment
Clin Cancer Res. 2015 Sep 1;21(17):3924-33.
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Highlights
Summary:•There is an underappreciated genomic heterogeneity associated with resistance to AZD9291 in NSCLC.
Clinical Significant:•Combination therapies can inhibit or prevent the emergence of multiple resistance mechanisms.
Ongoing Clinical Trials:•AZD9291 + PD-L1 antibody / MET inhibitor / MEK inhibitor (NCT02143466)
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Zuhua Chen@2015/10/28