The highlight of resistance mechanism of targeted therapy on clinical therapy Zuhua Chen Dep. of GI oncology

Targeted Therapy Drugs block the growth and spread of cancer by interfering with specific molecules that are involved in the growth, progression, and spread of cancer. Resistance

3 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 medicine Clonal 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?

4 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.

5 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.

6 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.

7 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.

8 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 medicine Acquired 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?

9 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.

10 AZD9291 resistance related molecular subtypes T790M(+)C797S(+)T790M(+)C797S(-)T790M(-)C797S(-) Nat Med. 2015; 21(7): 795–801.

11 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.

12 Allelic context of the C797Sm impacts sensitivity to treatment Clin Cancer Res Sep 1;21(17):

13 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: AZD PD-L1 antibody / MET inhibitor / MEK inhibitor (NCT )

Zuhua