Uncharted 3: Drake's Deception, as Naughty Dog co-president Evan Wells explains in a recent interview. "We're not dogmatic about anything," he tells CVG, when asked about the possibility of a "lead character" being killed off. "If that's what it takes then that's what it takes."
Thankfully, he doesn't spoil whether any main characters die -- he does explain, however, that Chloe and Elena "aren't the emphasis of the story the way they were in Uncharted 2." Rather, the focus of the third game is on the relationship between Nathan and his mentor, Victor "Sully" Sullivan. We have to imagine that Helen Mirren lookalike also plays a critical role, but Wells deftly avoids that plot thread as well. Gotta save something for November!