Antiproliferative Effects of Continued Mitogen-Activated Protein Kinase Pathway Inhibition following Acquired Resistance to BRAF and/or MEK Inhibition in Melanoma

Matteo S Carlino,Gulietta M Pupo,Stephanie Snoyman,Xu Dong Zhang,Therese M Becker,Richard F Kefford,Kavitha Gowrishankar,Catherine A.B Saunders,Helen Rizos,Georgina V Long,Robyn Saw

doi:10.1158/1535-7163.mct-13-0011

Abstract

Inhibitors of the mitogen-activated protein kinases (MAPK), BRAF, and MAP-ERK kinase (MEK) induce tumor regression in the majority of patients with BRAF-mutant metastatic melanoma. The clinical benefit of MAPK inhibitors is restricted by the development of acquired resistance with half of those who benefit having progressed by 6 to 7 months and long-term responders uncommon. There remains no agreed treatment strategy on disease progression in these patients. Without published evidence, fears of accelerated disease progression on inhibitor withdrawal have led to the continuation of drugs beyond formal disease progression. We now show that treatment with MAPK inhibitors beyond disease progression can provide significant clinical benefit, and the withdrawal of these inhibitors led to a marked increase in the rate of disease progression in two patients. We also show that MAPK inhibitors retain partial activity in acquired resistant melanoma by examining drug-resistant clones generated to dabrafenib, trametinib, or the combination of these drugs. All resistant sublines displayed a markedly slower rate of proliferation when exposed to MAPK inhibitors, and this coincided with a reduction in MAPK signaling, decrease in bromodeoxyuridine incorporation, and S-phase inhibition. This cytostatic effect was also associated with diminished levels of cyclin D1 and p-pRb. Two short-term melanoma cultures generated from resistant tumor biopsies also responded to MAPK inhibition, with comparable inhibitory changes in proliferation and MAPK signaling. These data provide a rationale for the continuation of BRAF and MEK inhibitors after disease progression and support the development of clinical trials to examine this strategy.

Highlights

Treatment of BRAF-mutant metastatic melanoma with the potent BRAF inhibitors, vemurafenib and dabrafenib, and the MAP–ERK kinase (MEK) inhibitor, trametinib, yields response rates of 25% to 60% and prolongs progression-free and overall survival [1,2,3,4,5,6,7]
A 50-year-old man with BRAFV600E-mutant metastatic melanoma was enrolled on part D of the phase I clinical trial of dabrafenib (75 mg twice daily) and trametinib (2 mg daily) in combination [31] and achieved RECIST 1.1 [38] partial response
The phase III clinical trial of vemurafenib confirmed that BRAF inhibitors are the standard of care in BRAFmutant metastatic melanoma [5]

Summary

Introduction

Treatment of BRAF-mutant metastatic melanoma with the potent BRAF inhibitors, vemurafenib and dabrafenib, and the MAP–ERK kinase (MEK) inhibitor, trametinib, yields response rates of 25% to 60% and prolongs progression-free and overall survival [1,2,3,4,5,6,7]. The clinical benefit associated with inhibition of the mitogen-activated protein kinase (MAPK) cascade is restricted by the development of acquired drug resistance, usually within 2 to 18 months of initial treatment. In vitro data indicate that PTEN loss [19], cyclin D1 overexpression [20], hepatocyte growth factor expression [21], fibroblast growth factor receptor 3 activation [22], and EGF receptor (EGFR) amplification [23] may contribute to MAPK inhibitor resistance. Clinical benefit beyond progression has been shown for the continuation of trastuzumab in HER-2–positive breast cancer [24, 25] and the dose escalation of imatinib in resistant gastrointestinal stromal tumors (GIST; refs. 26–29)

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Conclusion