Manu Tuilagi has been ruled out of England's Six Nations opener against Scotland on Saturday, while Alex Corbisiero will miss the entire championship.
Tuilagi has failed to recover from the ankle injury suffered in Leicester's Heineken Cup win over Toulouse earlier this month.
The 21-year-old centre had been given a deadline of Tuesday to prove his fitness, but the Calcutta Cup clash with Scotland has come too soon.
Tuilagi was one of England's star performers in December's win over New Zealand, scoring one try and creating two others, and his absence forces Lancaster to form a new centre partnership for the Twickenham clash with the Scots.
"By the end of the week we expect Manu to be running fully and changing direction," Lancaster said.
"The message I'm receiving from the medical team is that he will be training fully by Tuesday or Wednesday next week, but I'll need to make a call earlier in the week. He won't be training properly until at least Friday.
"Manu is a big loss - he was outstanding against New Zealand. But he missed the first two games of last year's Six Nations because of a hamstring and it's an opportunity for someone else.
"It's disappointing for him, but it's not a long-term injury so he'll be back soon."
England must decide whether to draft in Billy Twelvetrees or Jonathan Joseph to partner Brad Barritt, while fly-halves Toby Flood and Owen Farrell are also alternatives.
"We have a pretty good idea of how we'll rejig the midfield. We have our thoughts," Lancaster said. "It changes the emphasis a little bit, but it won't fundamentally affect the way we play.
"Brad will be in the equation and we need to make sure we can still break the gainline and have physical defenders. We've got to have the ability to get across the gainline and defend."
Meanwhile, Corbisiero underwent a procedure last week to clear out a "loose body" in his knee, and the Northampton-bound London Irish prop has had further surgery which has ruled him out of the entire tournament.
The American-born 24-year-old is likely to be sidelined for up to eight weeks and has been replaced in the squad by Sale front-rower Henry Thomas.
"The reality is the surgeons recommended two weeks rest and said it would then take six to eight weeks to be back playing, so that will rule him out of the Six Nations," said Lancaster.
"Hopefully he'll be back around the final game against Wales, but the reality is he'll have to play two or three Premiership games first.
"It's a shame because everything I heard about the operation was positive, but it's going to take a while to get right. Everyone's positive and upbeat about his recovery.
"Alex is a big loss, but Joe Marler has played well for Harlequins recently. Mako Vunipola is improving all the time and Nick Wood was outstanding for the Saxons."