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The pro-EU lawmakers join the so-called Independent Group founded by former Labour members of parliament on Tuesday.
In what is likely to be seen as a rebuke to Prime Minister Theresa May's efforts to unite the party, Anna Soubry, Sarah Wollaston and Heidi Allen announced their resignation in a joint statement on Wednesday.
"We no longer feel we can remain in the party of a government whose policies and priorities are so firmly in the grip of the ERG and DUP," they said, referring to a group of pro-Brexit lawmakers in the Conservative Party and the Northern Irish Democratic Unionist Party which props up the government in parliament.
"Brexit has re-defined the Conservative party — undoing all the efforts to modernize it. There has been a dismal failure to stand up to the hardline ERG, which operates openly as a party within a party, with its own leader, whip and policy."
It comes as at a time of heightened political tension in Britain, with less than six weeks to go before the world's fifth-largest economy is scheduled to leave the European Union.
"I am saddened by this decision — these are people who have given dedicated service to our party over many years, and I thank them for it," May said in a statement after the decision was made public.
"I am determined that under my leadership the Conservative Party will always offer the decent, moderate and patriotic politics that the people of this country deserve."
The departure of Soubry, Wollaston and Allen leaves May with an even more precarious majority in the House of Commons, at a time when the prime minister is hoping to win support for her Brexit deal over the coming weeks.
Last month, May's proposed Withdrawal Agreement was overwhelmingly rejected when euroskeptic and pro-EU lawmakers voted against a deal they claimed was the worst of all worlds.
May will hold fresh talks with the EU later on Wednesday, with a plan to secure legal assurances over the nature of the Irish border post-Brexit.
The U.K. leader is looking to renegotiate the so-called Irish "backstop" — a legally-binding insurance policy designed to prevent the return of customs checks on the border between Northern Ireland and the Republic of Ireland.
May is expected to request legally binding concessions that the backstop would not permanently bind the U.K. into a customs union.
Ahead of the talks, European Commission President Jean-Claude Juncker said he did not anticipate a "breakthrough."