Abstract B12: Overcoming acquired resistance to vemurafenib using clinically relevant PDX models of melanoma

• Published in: Molecular cancer therapeutics 2013-11, Vol.12 (11_Supplement), p.B12-B12
• Main Authors: Monks, Noel R., Monsma, David J., Cherba, David M., Eugster, Emily, Dylewski, Dawna, Winn, Mary E., Borgman, Andrew S., Davidson, Paula J., Peterson, Chelsea A., Pimiento, Jose M., Ivliev, Alexander E., Nikolsky, Yuri, Bessarabova, Marina, Calvert, Valerie S., Pierobon, Mariaelena, Petricoin, Emanuel F., Webb, Craig P., Nickoloff, Brian J.
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-13-B12

Development of resistance is a significant clinical problem for virtually all targeted cancer therapies. We have generated a reproducible, patient derived xenograft (PDX) model of acquired vemurafenib resistance to address these challenges. Continuous treatment of V600E melanoma tumors, caused synchronous tumor stasis for approximately 7 weeks, following which, all tumors displayed simultaneous resistance marked by rapid tumor growth. Additionally, this model maintains the resistance phenotype upon serial transplantation, providing a platform for testing rational drug selection. The fidelity of the PDX models was further confirmed using a BRAF V600V tumor which did not respond to vemurafenib. Onset of vemurafenib resistance is accompanied by increased phosphor-ERK signifying re-engagement of the MAPK signaling pathway and supporting MEK as a potential target. MEK inhibition in vemurafenib resistant tumors using PD0325901, resulted in rapid tumor shrinkage and dramatically reduced phosphor-ERK levels. Treatment of resistant tumors with PD0325901 alone, whilst leading to rapid tumor shrinkage, showed significant host toxicity and onset of acquired MEKi resistance. Interestingly, combination of vemurafenib + PD0325901 was non-toxic, and showed dramatic and sustained tumor suppression. Upon cessation of PD0325901 at 70 days the tumors remained undetectable for the duration of the study (>100 days). These data support the use of MEK inhibitors post-development of vemurafenib resistance and demonstrate that combination therapy mitigates systemic MEKi toxicity and results in persistent tumor inhibition/eradication. PDX models of acquired resistance provide a unique opportunity to bridge the gap between patients and the basic in vitro biology. Additionally, this PDX system allows the interrogation of the kinetics involved in the development of resistance by longitudinal tumor tissue sampling. Numerous mechanisms have been identified as potential causes of the resistance phenotype. Many have been identified in vitro but not all have been confirmed in patients. We detected no evidence of increased BRAF copy number or expression, although alternative BRAF splicing was identified in resistant tumors. Using differential gene expression accompanied by pathway and network analysis we identified distinct differences in the PDX tumors at various time points during the development of resistance. In particular, a potential role for interferon signaling in resistant tumors wa