Monday, November 30, 2015
Overcoming resistance to BRAFi in melanoma with the addition of Mcl-1 inhibitors?
For those with BRAF positive melanoma tumors....BRAFi, especially when combined with MEKi, can provide amazing responses. And while that combo, along with lessons learned in administration techniques, is allowing many to continue to respond longer, diminished response over time remains a problem for some. Here is a post that addressed that: BRAFi: What predicts resistance?
Here is an article with another theory/approach:
Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma. Oncotarget. Fofaria, Frederick, Sullivan, et al. 2015 Oct.
Melanoma harboring BRAF mutations frequently develop resistance to BRAF inhibitors, limiting the impact of treatment. Here, we establish a mechanism of resistance and subsequently identified a suitable drug combination to overcome resistance. Single treatment of BRAF mutant melanoma cell lines with vemufaenib or dabrafenib (BRAFi's) alone or in combination with trametinib (MEK1/2 inhibitor) resulted in overexpression of Mcl-1. [This in turn completely blocked BRAF and MEK inhibitors from killing melanoma cells.] Melanoma cells resistant to BRAF inhibitors showed massive expression of Mcl-1 as compared to respective sensitive cells. Silencing of Mcl-1 using siRNA completely sensitized resistant melanoma cells to growth suppression and induction of apoptosis by BRAFi [the BRAFi could stop growth and kill the melanoma cells once again!]. In vivo, vemurafenib resistant...[cells were implanted in mice]...and...showed substantial tumor growth inhibition when treated with a combination of vemurafenib and Mcl-1 inhibitor or siRNA. [Analysis showed] enhanced expression of Mcl-1... in vemurafenib resistant tumors [but] levels of Mcl-1 ... was diminished in the tumors of the mice treated with either of the combination. Biopsied tumors from the patients treated with or resistant to BRAFi revealed overexpression of Mcl-1. Results suggest that combining BRAFi with Mcl-1 inhibitors may have ... an advantage to melanoma patients with acquired resistance to BRAFi alone or in combination with MEKi.
So....in mice and men....folks with BRAF positive melanoma tumors who develop resistance to BRAFi or BRAFi combined with MEKi then have tumors that show excessive production of Mcl-1. When the mice with this problem were given vemurafenib combined with a Mcl-1 inhibitor or siRNA...their tumors no longer had the overexpression of Mcl-1 and would...in theory....again respond to BRAFi. This would be super cool if it works in peeps. Time will tell. Hang in there, ratties!!! - c