 promote the unbridled growth and proliferation of tumor cells. A growing roster of inhibitors, or targeted therapies, are either approved – like Gleevec (imatinib) and Tarceva (erlotinib) – or in clinical development.
But one common mutation has eluded inhibition: KRAS, which is mutated in about half of colon cancers and in many tumor types. “Figuring out how to target KRAS is one of the biggest challenges in cancer today,” says thoracic oncologist Jeffrey Engelman, MD, PhD (MGH). Engelman recently developed a new strategy that foils KRAS indirectly by double-teaming what it activates. Mutant KRAS activates the MEK growth signaling pathway. However, MEK inhibitors alone have not proven effective in KRAS mutated cancers, so another gene might be conspiring with MEK to evade cell death. Engelman and his colleagues decided to use MEK inhibition as a backbone for building a combination therapy.
They used a technique called RNA interference (RNAi) to silence the expression of different genes in different cells in an unbiased fashion. They grew these cells with and without exposure to a MEK inhibitor, reasoning that the cells that died with MEK inhibition had lost a MEK co-conspirator gene. This led to the BCL-XL gene, which researchers had previously shown allows cells to override apoptosis, the cell death pathway. Engelman’s team demonstrated in cell cultures and then in mice that inhibiting both MEK and BCL-XL was much more lethal to cancer cells than inhibiting just one or the other. In genetically engineered mouse models of human KRAS mutant cancer developed by Kwok Wong, MD, PhD (DFCI), the combined therapy demonstrated significant activity in shrinking tumors, providing greater support for the promise of this therapeutic approach.
Drugs that inhibit MEK (trametinib) and BCL-XL (navitoclax) are in clinical testing separately, which should accelerate the path toward a combination trial. If this strategy succeeds, it would be a big advance for the many cancer patients with KRAS mutations. Still, it may not benefit all KRAS mutant cancers equally. The combined inhibition worked better at shrinking tumors comprised of differentiated epithelial cells compared to those that displayed mesenchymal features. This distinction could provide a clinical biomarker for predicting which patients may respond to the combination – predictability that is key to personalized cancer therapy.
A Mixed and Evolving Population
Just as lung tumors, for example, have genetic heterogeneity, an individual tumor has cellular heterogeneity, with different cells playing different roles in growth, invasion, drug sensitivity, and relapse. David Langenau, PhD (MGH), is exploring this concept using zebrafish to visualize the dynamic process of tumor development and relapse. (See accompanying article Visualizing the Birth of Cancer in Zebrafish.) “In assessing genes associated with relapse in humans, we often compare the primary tumor to the relapsed tumor and assess how the whole bulk of the tumor is different at relapse,” he explains. “But each cancer cell could have different mutations at relapse, and we don’t know which mutations are drivers of relapse growth and which are passenger mutations that have no effect on tumor growth."
To gain a more linear view, Langenau transplanted a single leukemia cell into zebrafish and tracked its evolution into the full spectrum of leukemia cells over time. “Amazingly only a handful of genes – about 19 – seemed important to the evolution,” he says, and they were active in only a minority of tumor cells. Those cells may be tumor-propagating cells, with some properties of stem cells in their ability to differentiate into the other heterogeneous cell types of the tumor, and they may be responsible for tumorigenesis, metastasis, resistance, and/or relapse. Langenau is now testing these genes to see if they are potential targets for therapy in leukemia.
Dark Matter Does Matter
Until recently, most gene sequencing projects focused on protein-coding regions, to great payoff. For example, determining that the majority of meta