Pharma Strategy Blog

Many of you will have been following the ongoing story of the discovery of activating V600E mutations in BRAF in greater than 50% of melanomas. As a result, BRAF inhibitors such as PLX4032 have emerged in melanoma but ultimately, we have also seen how resistance unfortunately sets in after 6 to 9 months of therapy despite some impressive initial results.  In addition, approximately 20% of patients don’t respond at all – the key question is why?

Previously, we have discussed several mechanism of resistance, namely AKT and MEK, which has lead to new clinical trial combinations of BRAF plus an AKT or MEK inhibitor (e.g. see this trial) to see if this approach can delay the development of resistance and thus improve the time to progression further.   A background on MEK inhibition can also be found here.

A new article published this month in Cancer Research from Paraiso et al., (2011) suggests another possible mechanism of resistance with BRAF inhibition may also be involved, namely loss of PTEN function (see references below).  They looked at what might happen with a new second generation BRAF inhibitor, PLX4720.

In this new research, some interesting findings emerged:

“We identify loss of PTEN expression, observed in >10% of melanoma specimens, as being responsible for increased PI3K/AKT signaling when BRAF is inhibited.

We further show that PTEN loss contributes to the intrinsic resistance of BRAF V600E-mutated melanoma cell lines to PLX4720 by suppressing the expression of the pro-apoptotic protein BIM.”

They essentially found that increased AKT signaling occurs with PTEN loss:

“Treatment of the PTEN+/- cell line panels with PLX4720 increased pPDK1 and pAKT signaling only in the melanoma cell lines lacking PTEN expression.”

They also observed that:

“Loss of PTEN contributes to intrinsic BRAF inhibitor resistance via the suppression of BIM-mediated apoptosis.”

Some of you may be wondering how these findings can be used to design new therapeutic strategies.  However, loss of PTEN function and heightened BIM expression isn’t something that can be changed directly, but rather, indirectly:

“Dual treatment of PTEN- cells with PLX4720 and a PI3K inhibitor enhanced BIM expression at both the mRNA and protein level and increased the level of apoptosis through a mechanism involving AKT3 and the activation of FOXO3a.”

There are some new trials open with either single agents or combination trials in this area, such as the following selection (by no means exhaustive):

1. GSK2118436 (A BRAF and MEK/ERK inhibitor) – single agent trial interim data was previously presented at ASCO and ESMO last year.  The initial data in melanoma related brain mets presented at ESMO was stunning.
2. BKM120 (PI3K) and GSK1120212 (MEK) – combination trial in advanced solid tumours with RAS/RAF mutations.
3. GDC-0941 (PI3K) plus GDC-0973 (MEK) – combination trial in advanced solid tumours.
4. GSK1120212 and GSK2141795 phase I safety and PK trial.

I think this is one area in oncology where the research into the underlying biology and mechanism of resistance is almost keeping pace with the clinical research, which is great news for patients!   More vibrant data may begin to emerge soon at ASCO in June and ESMO in September, so hopefully we won’t have long to wait for a new update on progress.

A big question that remains to be answered though, is figuring out which patients should get what combination and in what sequence?  Time will tell, but we have a while to go before we understand things better.

References:

Paraiso, K., Xiang, Y., Rebecca, V., Abel, E., Chen, A., Munko, A., Wood, E., Fedorenko, I., Sondak, V., Anderson, A., Ribas, A., Dalla Palma, M., Nathanson, K., Koomen, J., Messina, J., & Smalley, K. (2011). PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression Cancer Research DOI: 10.1158/0008-5472.CAN-10-2954