The Ligue 1 club confirmed the decision on Thursday, announcing in an official statement: "Racing Club de Lens announces that Yannick Cahuzac has been relieved of his duties as head coach of the first team."
The Como rout, which equalled the heaviest defeat in Champions League history, proved to be the breaking point for the club's hierarchy.
It came during a miserable spell that also included a 1-0 defeat against local rivals Lille and a 2-1 loss to Marseille on Sunday.
The Marseille defeat was particularly painful, with Lens conceding an early goal following a costly defensive mistake. Frustrated supporters also displayed a banner declaring: "You are the shame of 120 years of history."
The dismissal represents a dramatic fall for a club that enjoyed an outstanding campaign last season, winning the French Cup and finishing runners-up to Paris Saint-Germain in Ligue 1.
Cahuzac is the second manager to lose his job this season. Dino Toppmoeller was appointed during the close season after Pierre Sage departed for Crystal Palace, but lasted just six matches before being dismissed in September.
Cahuzac, who had served as Toppmoeller's assistant, was promoted to the top job but failed to turn the club's fortunes around. He won only three of his nine matches in charge, losing the other six in all competitions.
Lens are now 11th in Ligue 1 with 13 points and sit 33rd in the Champions League standings with just three points.
They host Toulouse next week as the club attempts to halt its alarming slide and restore some stability after another change in the dugout.
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Steven Gerrard believes Lamine Yamal has the potential to become one of football's greatest players, claiming the Barcelona teenager is already more advanced than Lionel Messi and Cristiano Ronaldo were at the same age.
Liverpool manager Andoni Iraola has urged his players to remain calm and keep perspective after consecutive defeats against Arsenal and Fenerbahce threatened to derail their positive start to the season.
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