Slide 1: Antitumor activity of Tipifarnib and PI3K Pathway inhibitors in HRAS-associated HNSCC
Antitumor activity of Tipifarnib and PI3K Pathway inhibitors in HRAS- associated HNSCC Francis J. Burrows VP Translational Research Kura Oncology San Diego, CA
Slide 2: Financial relationships disclosure
Francis Burrows I have the following financial relationships to disclose: Employee of: Kura Oncology I will not discuss off label use and/or investigational use in my presentation.
Slide 3: Introduction
Introduction • HRAS is mutated in ~5% and overexpressed in ~30% of HNSCC • PIK3CA is commonly activated (~30%) by GOF mutations or gene amplification • HRAS and PI3K pathways cooperate and crosstalk in driving tumor progression in SCCs and resistance to inhibitors of respective pathways • Here we ex
Slide 4: Some HRAS-high HNSCC PDX are sensitive to tipifarnib
Some HRAShigh HNSCC PDX are sensitive to tipifarnib HRASlow HRAShigh Vehicle Tipifarnib • Tipifarnib displayed robust inhibition of tumor growth in a subset of PDX models overexpressing wild-type HRAS • In preliminary combination studies, tipifarnib sensitized HRAS-WT-high HNSCC PDX to a variety of
Slide 5: Tipifarnib–alpelisib combination reduces HNSCC viability via effects on PI3K and MAPK signaling
Tipifarnib–alpelisib combination reduces HNSCC viability via effects on PI3K and MAPK signaling HSC-2 HSC-4 HSC-3 Cell line viability HSC-4 HSC-4 HSC-4 Oncogenic signaling p-ERK p-AKT p-S6 • The combination of tipifarnib and alpelisib enhances inhibition of cellular viability in these monolayer cult
Slide 6: HRAS and PIK3CA dysregulated HNSCC lines are sensitive to tipifarnib-alpelisib combination
HRAS and PIK3CA dysregulated HNSCC lines are sensitive to tipifarnib-alpelisib combination Tipifarnib (nM) Tipifarnib (nM) Tipifarnib (nM) 0 1 2.3 5.6 13.3 31.6 75 178 422 1000 0 1 2.3 5.6 13.3 31.6 75 178 422 1000 0 1 2.3 5.6 13.3 31.6 75 178 422 1000 0 0 0 Alpelisib (nM) 100 Alpelisib (nM) 100 100
Slide 7: HRAS and PIK3CA dysregulated HNSCC PDX are sensitive to tipifarnib-alpelisib combination
HRAS and PIK3CA dysregulated HNSCC PDX are sensitive to tipifarnib-alpelisib combination • The tipifarnib-alpelisib combination regimen is superior to either single agent in HRAS-overexpressing HNSCC PDX harboring mutant, amplified or WT PIK3CA • IHC staining of PIK3CAmut, HRAShigh HN3690 PDX tumors
Slide 8: Synchronous dosing with alpelisib is superior to intermittent dosing
Synchronous dosing of tipifarnib and alpelisib is superior to intermittent dosing 1600 HRAS-mutant 1000 HRAS-mutant 1400 1400 900 PIK3CA-mutant PIK3CA-mutant 1200 800 1200 1000 700 1000 600 800 800 500 600 600 400 300 400 400 Mean Tumor Volume ± SEM 200 200 200 100 HRAShigh 0 0 0 0 5 10 15 20 25 30
Slide 9: Conclusions
Conclusions • HRAS, both in the mutant and overexpressed form, acts as a key node at the center of HNSCC tumor biology for a significant subset of patients • HRAS-MAPK and PI3K-AKT-mTOR are complementary pathways in HNSCC, each providing compensatory mechanisms of resistance to single agent inhibiti