Emergence of resistance to tyrosine kinase inhibitors in non-small-cell lung cancer can be delayed by an upfront combination with the HSP90 inhibitor onalespib.
BACKGROUND
Tyrosine kinase inhibitors, such as crizotinib and erlotinib, are widely used to treat non-small-cell lung cancer, but after initial response, relapse is common because of the emergence of resistance through multiple mechanisms. Here, we investigated whether a frontline combination with an HSP90 inhibitor could delay the emergence of resistance to these inhibitors in preclinical lung cancer models.


METHODS
The HSP90 inhibitor, onalespib, was combined with either crizotinib or erlotinib in ALK- or EGFR-activated xenograft models respectively (H2228, HCC827).


RESULTS
In both models, after initial response to the monotherapy kinase inhibitors, tumour relapse was observed. In contrast, tumour growth remained inhibited when treated with an onalespib/kinase inhibitor combination. Analysis of H2228 tumours, which had relapsed on crizotinib monotherapy, identified a number of clinically relevant crizotinib resistance mechanisms, suggesting that HSP90 inhibitor treatment was capable of suppressing multiple mechanisms of resistance. Resistant cell lines, derived from these tumours, retained sensitivity to onalespib (proliferation and signalling pathways were inhibited), indicating that, despite their resistance to crizotinib, they were still sensitive to HSP90 inhibition.


CONCLUSIONS
Together, these preclinical data suggest that frontline combination with an HSP90 inhibitor may be a method for delaying the emergence of resistance to targeted therapies.
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
Aurelie
A
Courtin
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
Tomoko
T
Smyth
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
Keisha
K
Hearn
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
Harpreet K
HK
Saini
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
Neil T
NT
Thompson
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
John F
JF
Lyons
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
Nicola G
NG
Wallis
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D054833:Isoindoles / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D020360:Neoadjuvant Therapy / Q000379:methods; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D000069347:Erlotinib Hydrochloride; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone
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