Receptor tyrosine kinases as therapeutic targets for cancer John Heymach, M.D., Ph.D. Depts. of Thoracic/Head and Neck Medical Oncology and Cancer Biology University of Texas M.D. Anderson Cancer Center March 13, 2009
1. Target not critical for a given tumor (primary resistance)
2. Incomplete receptor inhibition
Inhibitor not sufficiently potent
Secondary mutations that prevent binding of inhibitor (i.e. T790M mutation in lung cancer prevents gefitnib or erlotinib from inhibiting EGFR)
3. Target bypass: the tumor circumvents the inhibited pathway by activation of other pathways (i.e. MET)
Potential mechanisms of resistance to targeted agents R R Ligand R R Ligand Pathway X Effect (I.e. tumor cell survival) Pathway X Effect (I.e. tumor cell survival) 1. Incomplete target inhibition Effective target inhibition X (partial) inhibitor
Potential mechanisms of resistance to targeted agents R R Ligand R R Ligand Pathway X Effect (I.e. tumor cell survival) R R Ligand Pathway X Effect (I.e. tumor cell survival) Pathway X Effect (I.e. tumor cell survival) R2 R2 Ligand 2 1. Incomplete target inhibition 2. “Target bypass” Effective target inhibition X X Pathway Y A B
Approaches to combating resistance R R Ligand R R Ligand Pathway X Effect (I.e. tumor cell survival) Pathway X Effect (I.e. tumor cell survival) R2 R2 Ligand 2 1. Incomplete target inhibition 2. “Target bypass” X Pathway Y A B Add additional inhibitor or try more potent inhibitor for same target
Approaches to combating resistance R R Ligand R R Ligand Pathway X Effect (I.e. tumor cell survival) Pathway X Effect (I.e. tumor cell survival) R2 R2 Ligand 2 1. Incomplete target inhibition 2. “Target bypass” X Pathway Y A B Inhibit downstream or bypass pathways
All recent randomized studies have similar results
No clear efficacy benefit for nonplatinum combinations or triplet combinations
Are we approaching the ceiling for improved benefit from combination chemotherapy regimens? Schiller JH et al. N Engl J Med . 2002;346:92-98. Cisplatin/Paclitaxel Cisplatin/Gemcitabine Cisplatin/Docetaxel Carboplatin/Paclitaxel 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 Months Stage IIIB/IV Patient Survival, % ECOG 1594
NCI Canada BR.21 Advanced NSCLC Tarceva vs Placebo Phase III Trial Previously Treated Advanced NSCLC N = 638 Stratified by : Center PS, 0/1 vs 2/3 Response to prior Rx (CR/PR:SD:PD) Prior regimens, (1 vs 2) Prior platinum, (Yes vs no) Shepherd, et al. PASCO 2004 Erlotinib 150 mg PO QD R A N D O M I Z E D Placebo PO QD 2:1 randomization
Overall Survival *Adjusted for stratification factors at randomization, and HER1/EGFR status. HR = hazard ratio. TARCEVA ™ (erlotinib) PI. TARCEVA (n=488) Placebo (n=243) Median survival (mo) 1 - year survival (%) Months Survival distribution function 1.00 0 5 10 15 20 25 30 0.75 0.50 0.25 0 TARCEVA Placebo 6.7 4.7 31.2 P <0.001 * HR=0.73 (95% CI, 0.61-0.86) 21.5
Analysis of tumor from patients with major response to EGFR inhibitors
Approximately 10-20% of patients had dramatic tumor shrinkage after treatment (major response)
In majority of tumors from patients with major response, mutations in EGFR tyrosine kinase domain observed (exon 19 deletion, point mutation)
Mutation led to constitutive activation of EGFR and increased sensitivity to EGFR inhibition.
Tumors with amplification of EGFR may also have increased sensitivity
Patients who never smoked, or were of Asian origin, had a high frequency of EGFR mutations.
(Paez et al, Science, 2003; Lynch et al, NEJM, 2003)
Never smokers: overall survival- erlotinib vs Placebo 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 Survival rate Erlotinib Placebo Months on study Herbst et al., ASCO 2004
Secondary mutations in EGFR (T790M) lead to acquired resistance to EGFR TKIs Kobayashi et al, NEJM 2005
Secondary mutations in EGFR (T790M) lead to acquired resistance to EGFR TKIs Kobayashi et al, NEJM 2005 T790M mutation
Amplifications of MET receptor lead to resistance in previously EGFR-addicted NSCLC cells. Engelman et al, Science, 2007
Pivotal role of VEGF in tumor angiogenesis 2. VEGF increases endothelial protease expression 1. Tumor secretes VEGF 4.VEGF induces mobilization and differentiation of BM- derived CEPs 3. Endothelial cell migration proliferation, and capillary tube formation promoted by VEGF Bone marrow
Different approaches to inhibition of VEGF signaling Ligand sequestration: MAbs, soluble receptors (i.e. bevacizumab) GRB2 SOS ras PLC p85 Inhibition of tyrosine phosphorylation and downstream signaling inhibition Transcription factor inhibition Tyrosine kinase inhibition: TKIs TKI tyrosine kinase inhibitor Receptor blocking: MAbs
SU11248: Multitargeted Receptor Tyrosine Kinase Inhibitor VEGFR-1 VEGFR-2 VEGFR-3 Fms PDGFR PDGFR CSF1R KIT FLT3 Split Kinase Domain RTKs Mendel DB, et al. Clin Cancer Res 2003;9:327–37 *Receptor phosphorylation FLT3 (WT) 0.25 KIT 0.01 VEGFR-2 0.009 *Cellular IC 50 (µM) PDGFR 0.008 EGFR 8.9 MET 12.0 VEGFR-2 0.009 PDGFR 0.008 FGFR1 0.83 EGFR >10 Enzymatic K i (µM) VEGFR-3 0.017 N H O N H F N H O N OH COOH HOOC H
LSC analysis of PDGFR-beta and VEGFR-2 phosphorylation after treatment of GIST patients with SU11248 for 10-14 days Patients (n=20) PD SD PR PD = progressive disease; SD = stable disease; PR = partial response % change in phosphorylation post-treatment Davis et al, ECCO 2005 -
Lessons from tumor-based biomarkers of activity
For SU5416/SU6668, lack of clinical activity likely due, at least in part, to incomplete target inhibition.
It is critical to not only identify important targets, but also to determine the duration and degree of target inhibition needed for anti-tumor activity.
2. SU11248-treated GIST patients with clinical benefit had a:
greater post-treatment induction in TEC apoptosis (9.55 vs 1.78) and TC apoptosis than patients with progressive disease
greater degree (but not complete) inhibition of PDGFR- β and VEGFR phosphorylation.
There is likely to be room for improvement with more potent inhibitors or combinations.