The highlight of resistance mechanism of targeted therapy on clinical therapy

Zuhua ChenDep. of GI oncology

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)

Zuhua Chen@2015/10/28