What they saw was that one receptor in particularPDGFRβwas highly expressed and active in all treated tumor cells, but virtually absent in tumors that were spared treatment. The researchers detected the same pattern in cultures of cells derived from a variety of glioblastoma tumors. This suggested that cancer cells in which EGFR signaling is blocked respond by expressing PDGFRβ to compensate for the loss of that critical signal.
To determine whether the phenomenon occurred in patients as well, the team examined tumor samples collected in a clinical trial of another EGFR-targeting drug named lapatinib. "Across tumors," says Mischel, "we saw a reciprocal relationship between the activation of PDGFRβ and the mutant form of the EGFR. This established that what we were seeing in lab experiments was happening in people actually undergoing treatment with EGFR targeting drugs."
Using pharmacologic and genetic techniques to tease apart the signaling pathways responsible for this effect, the researchers found that two distinct biochemical circuits switched on by EGFR suppressed the expression of the PDGFRβ gene. One is mediated by a protein named mTORC1, and another by a protein named MEK. "When one blocks EGFR signaling with a drug," explains Mischel, "that repression is lifted. But, more importantly, these tumors do not need PDGFRβ signaling to survive until you block EGFR." At that point, the tumors become highly dependent on PDGFRβ.
"It's almost like a game of whack-a-mole," says Mischel. "You use a drug to suppress a choice target, and something else pops up to take its place and keep the cells alivein this case a growth factor receptor that is perfectly normal in physiological terms." Notably, such resistance mechanisms, unlike genetic mutation, are very difficult to an
|Contact: Rachel Steinhardt|
Ludwig Institute for Cancer Research