Labour MPs from the borough have signed a letter to party leader Jeremy Corbyn and his shadow cabinet warning against a second referendum and saying Brexit must happen.
Wigan MP Lisa Nandy and her colleagues for Makerfield and Leigh Yvonne Fovargue and Jo Platt have all signed the letter, warning another public vote on Britain's departure from the European Union (EU) would be "toxic".
The politicians say it is the Brexit Party that poses a bigger threat to Labour's heartland constituencies, like those in the borough, than pro-Remain parties such as the Liberal Democrats and the Greens.
The MPs have written to the party's leadership following local and European elections in which they say the party suffered heavy losses in pro-Leave areas and the Peterborough by-election in which the red rosette scraped home ahead of Nigel Farage's recently-formed outfit and the Conservatives.
It also follows loud calls for Labour to adopt a more pro-Remain position as the Conservative Party holds its leadership campaign.
However, the letter also says the party must take steps to avoid a no-deal departure from the EU.
The letter said: "Our party was devastated in the local elections in longstanding Labour-held councils.
"The strength of the Brexit Party in Labour heartland areas in the European elections revealed a much more potent threat than either the Liberals or Greens present.
"The Peterborough by-election result, with Labour's vote share down 17 per cent and the Brexit Party coming so close, gives a stark warning of what could happen in Tory-Labour marginals, the majority of which are Leave seats.
"Labour's briefing note to Peterborough canvassers sought to assure voters that Brexit will not be stopped. Brexit must happen. The UK must leave, and do so without further undue delay.
"A commitment to a second referendum would be toxic to our bedrock Labour voters, driving a wedge between them and our party, jeopardising our role as a party of the whole nation, and giving the populist right an even greater platform in our heartlands.
"Rejecting any form of Brexit in the hope of securing a perfect deal risks the worst outcome - a No Deal Brexit."
West Lancashire MP Rosie Cooper has also signed the letter, which has the support of 26 Labour MPs.