Pathway analysis has become a significant element in
developing therapeutics for various cancers. Melanoma was first attacked using
the BRAF V600 mutation as a target and then the MEK change was added. However
as is seen in many cancers other mutations then occur making the initial
therapeutic no longer functional. The pathways for melanoma are shown below.
In a recent paper by Villanueva et al the authors have
demonstrated that a tri-partite treatment has efficacy in melanoma.
They state:
Although BRAF and MEK inhibitors have proven clinical
benefits in melanoma, most patients develop resistance. We report a de novo
MEK2- Q60P mutation and BRAF gain in a melanoma from a patient who progressed
on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor
dabrafenib.
We also identified the same MEK2-Q60P mutation along with
BRAF amplification in a xenograft tumor derived from a second melanoma patient
resistant to the combination of dabrafenib and trametinib. Melanoma cells
chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and
BRAF-V600E amplification, which conferred resistance to MEK and BRAF
inhibitors. The resistant cells had sustained MAPK activation and persistent
phosphorylation of S6K.
A triple combination of dabrafenib, trametinib, and the
PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence,
concurrent genetic events that sustain MAPK signaling can underlie resistance
to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to
overcome it.
This is an excellent example of a triple therapeutic attack
on a cancer. The problem is that the malignant cells seem always to change
again so in effect one must continually measure the cell and add a new element
to the treatment. It would be useful if one better understood the natural
evolution, if such an assumption is viable.
The authors conclude:
Combination therapy with BRAF and MEK inhibitors appears
to be more effective than single-agent approaches; however, this combination
could have limited activity in resistant tumors, particularly in the context of
concurrent resistance mechanisms that hyperactivate the MAPK pathway. Our
studies suggest that this combination is likely to be more effective if used as
first-line therapy before resistance emerges. Moreover, effective therapies are
sorely needed for patients who progress on BRAF/MEK inhibitors.
Targeting the MAPK pathway downstream of MEK at the level
of ERK, S6K, or RSK is a potential approach to overcome resistance. We have
demonstrated that a triple combination strategy using BRAF, MEK, and PI3K/mTOR
inhibitors led to sustained tumor growth control, with no overt signs of
toxicity. This type of strategy will need to be further refined and evaluated.
Various issues that could be explored include alternative dose scheduling, drug
sequencing, drug combinations comprising specific inhibitors of downstream
targets, and efficacy in tumors bearing other mechanisms of BRAF- and/or
MEK-inhibitor resistance or other tumor types.
Alternative combination strategies, such as the one we
tested, warrant preclinical and clinical investigation as potential approaches
to treat patients refractory to BRAF and MEK inhibitors.
The opportunity exhibited by this approach is significant.
However it raises several questions.
1. Is there a “natural” and predictable progression of
melanoma mutations which can then be therapeutically addressed? Namely, can one
anticipate future changes and perhaps deal with them early?
2. How does one know what the full complements of changes
are in a single patient? We can extract part of a localized tumor and from that
sample and determine but what of the cells that lodged in the brain for
example. We know that cells which cross the blood brain barrier exhibit
differing surface markers and these may very well be reflective of further
mutations. One may then seek to target these as well, which is a significant
challenge.
3. Back to the old stem cell problem, namely if there are
stem cells in melanoma then do we target them and if so how do we identify
them? Are the cells we target merely subservient to the stem cell which avoids
being targeted?
4. Does this approach mandate a therapeutic strategy which is
truly patient specific? Namely do we now genetically deal with each patient
separately or are their reasonably large classes?
There are substantial issues but the results in this paper a
quite significant and promising.
References
Villaneuva, J., et al, Concurrent MEK2 Mutation and BRAF
Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma, Cell
Reports 4, 1–10, September 26, 2013.
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