At AACR last year, one of the most revealing presentations was on metastatic melanoma, specifically, some elegant research by Meghna Das Thakur (NIBR) demonstrating that intermittent pulsing of vemurafenib (a BRAF V600E inhibitor) led to less resistance than inhibiting the target 24/7.

Many of us wondered whether such a pulsing approach would be useful for other tyrosine kinase inhibitors (TKIs).

Fast forward to this week.

CD current Jan 2014Neal Rosen’s lab at MSKCC has an interesting new paper out looking at the effects of pulse dosing with PI3K and ERK inhibition, since targeting both has long been suspected to be key in overcoming cross-resistance.

Recall that despite promising preclinical research, most of the early patient trials looking at targeting the PI3K-Akt-mTOR and RAS-RAF-MEK-ERK pathways in combination were, however, disappointing to say the least, both in terms of the side effect profile, and also with respect to clinical efficacy.

These results also applied to combinations with chemotherapy, which were added to either agent to try and induce cell death via apoptosis.

We know that the PI3K pathway is dysregulated in many cancers, so why have the combinations tried to date produced less than optimal results?

Well, Will et al., (2014) showed that:

  1. RAS-ERK pathway is a key downstream effector pathway of oncogenic PI3K
  2. ERK inhibition is required for apoptosis (cell death) to occur with a PI3K inhibitor
  3. It is important to coordinate downregulation of AKT and ERK since both are necessary for induction of apoptosis and antitumor activity
  4. Such an effect can be achieved with intermittent dosing, which will also likely decrease toxicity and allow administration of therapeutic doses

Ah so the same concept that Das explored in metastatic melanoma could also have potential with PI3K and MEK inhibition!

I find this approach fascinating because in the past, when I queried whether we needed to hit two targets maximally and continuously, rather than look at intermittent or minimally effective dosing (MED), industry people were up in arms and sent me more heated emails on this topic than anything else we’ve ever blogged about!

Meanwhile, Rosen himself hinted at this solution in a talk at the AACR Molecular Targets meeting in Boston last year and said a publication was underway to explain their findings. Generally, I don’t report on unpublished findings out of respect to the scientists and thus didn’t mention it in our extensive AACR Targets Coverage, but am delighted this is now a topic for more public discussion.

Part of the conundrum was articulated by Will et al., (2014) in their author manauscript (see below for the link under the Cancer Discovery Online First Section this month):

“Since mTOR and AKT inhibitors reactivate PI3K signaling, we asked whether PI3K inhibitors have more significant antitumor activity, perhaps by inhibiting other PI3K targets in addition to AKT/mTOR.

Selective PI3K and AKT inhibitors were compared in tumors with activation of PI3K pathway signaling in order to assess differences in the biochemical and biologic consequences of their inhibition. Both inhibitors effectively inhibited downstream targets of AKT, relieved feedback inhibition of growth factor receptors, and inhibited cell growth. However, in HER2-dependent breast cancers, PI3K inhibitors, but not AKT inhibitors, caused the rapid induction of a significant degree of apoptosis.

We find that, whereas AKT inhibitors inhibit AKT/mTOR and activate ERK signaling, PI3K inhibitors inhibit both. They cause durable inhibition of AKT signaling but also transient inhibition of RAS activation and ERK signaling, both of which are required for induction of apoptosis. Moreover, induction of apoptosis by an AKT inhibitor is significantly enhanced when combined with a MEK inhibitor.

Our results show that PI3K is upstream of wild type RAS as well as AKT/mTOR, and this causes the therapeutic consequences of PI3K inhibition to be significantly greater than those of AKT inhibition.”

A number of different inhibitors of PI3K, AKT, mTOR and MEK were explored in this research, so the results are not limited to one or two.

One important question that the group sought to address the inhibition issue:

“PI3K inhibitors cause rapid inhibition of ERK in breast cancer cells with HER2 amplification, but P-ERK levels rebound fairly quickly. Even so, this transient inhibition is required for significant induction of apoptosis by these drugs. We asked whether more complete and sustained inhibition of ERK might enhance induction of cell death by the PI3K inhibitor.”

They found that:

“These results suggest that, in some cells, inhibition of other non-AKT targets of PI3K contribute to induction of apoptosis, or that stronger MEK inhibition is required to fully activate apoptosis. Combined inhibition of MEK and PI3K caused more apoptosis than any of the other treatments in all three models.”

This lead to further work and the finding that:

“Pulsatile PI3K inhibition caused initial tumor regression and significantly suppressed tumor growth. The effectiveness of intermittent administration of the PI3K inhibitor and its superior antitumor activity compared to AKT inhibition were confirmed in another HER2 amplified, PI3K mutant breast cancer model, MDA-MB–361.”

The reason for this?

“We hypothesized that the effectiveness of PI3K inhibition was due in part to its combined inhibition of ERK and AKT.”

The Will et al., (2014) article is available online and open access (see here for direct link) – I highly recommend those interested in this field checking it out and reading the nuggets for yourself, it’s well written and easy to follow.

What does all this mean?

It would be hard for me to improve on Will et al., (2014) conclusion that:

“Recently, treatment with more selective PI3K inhibitors has led to greater therapeutic efficacy in lymphomas and in breast cancer with PI3K mutation or HER2 amplification. The ability of any PI3K inhibitor to inhibit signaling adequately is limited by physiologic toxicity. Moreover, attempts to combine MEK inhibitors with `dual specificity’ PI3K or AKT inhibitors have been complicated by severe toxicity at modest doses of these drugs.

The idea that the pathway must be inhibited continuously dominates the clinical development of these drugs.

Our finding that transient inhibition of PI3K is effective in in vivo models suggests that periodic rather than continuous target inhibition is an alternative strategy that would allow adequate pathway inhibition without causing inordinate toxicity or chronic feedback reactivation of receptors.

Thus, combining PI3K inhibitors, MEK inhibitors and, perhaps, inhibitors of key reactivated RTKs, and administering them at high dose on intermittent schedules may be a more effective therapeutic strategy for these tumors.”

Overall, don’t be surprised to suddenly see new clinical trials emerge evaluating intermittent dosing with PI3K and MEK inhibitors. The only questions in my mind is who will be the first to go this route and who will be able demonstrate superior efficacy and tolerability in patients?

The scientific rationale is very solid for intermittent dosing with BRAF V600E inhibitors and now with the combination with a PI3K plus a MEK inhibitor; it will be really interesting to see if such an approach will translate successfully in the clinic.  I hope it does because improving outcomes is ultimately what we are all here for.


ResearchBlogging.orgMarie Will, Alice Can Ran Qin, Weiyi Toy, Zhan Yao, Vanessa Rodrik-Outmezguine, Claudia Schneider, Xiaodong Huang, Prashant Monian, Xuejun Jiang, Elisa de Stanchina, Jose Baselga, Ningshu Liu, Sarat Chandarlapaty, & Neal Rosen (2014). Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of
RAS-ERK signaling Cancer Discovery : 10.1158/2159–8290.CD–13–0611