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In 2005 Lowe starred in the miniseries Beach Girls on the Lifetime network, based on the Luanne Rice novel of the same name.The series premiere received the highest ratings for a movie premiere in Lifetime history.Lowe and series creator Aaron Sorkin soon found themselves at odds over the network's meddling with the show, most notably the network demanding changes in the Sam Seaborn character.Eventually, Lowe left the series, not long before Sorkin and director/executive producer Thomas Schlamme unceremoniously quit over a dispute with NBC.After leaving the show, Lowe was the star and executive producer of a failed NBC drama, The Lyon's Den (2003). Although Lowe had expressed unhappiness about his decreased role on that show at the time of his departure, he has now repeatedly said that any animosity between them is over and that he was pleased to be working once more with Sorkin, whose talents as a writer Lowe highly regards. Derek Shepherd of Grey's Anatomy, which eventually went to Patrick Dempsey.Despite his two cancelled TV series and flops like View From the Top and the made-for-TV movie Perfect Strangers during his post–West Wing run, Lowe found success in the TV miniseries genre.

In 2006, it was announced that Lowe would join the cast of Brothers & Sisters for a guest run of several episodes.He continued to appear in the series until the end of the 2009–10 season.Unhappy with the stories and his lack of screen time in the fourth season, Lowe announced he would leave.In his autobiography Stories I Only Tell My Friends, he wrote regarding Sheen, "We were both nerds [...] he wanted to be a baseball player." One of Lowe's earliest roles came in the 1983 TV film Thursday's Child, for which he received his first Golden Globe Award nomination for Best Supporting Actor in a Series, Miniseries, or Television Film.His breakthrough role was his big screen debut in 1983, when he and Emilio Estevez were cast in Francis Ford Coppola's The Outsiders. Elmo's Fire, making them the two more prominent actors from the group known as the Brat Pack. followed, with Demi Moore (who had starred alongside Lowe in St. He then received his second Golden Globe Award nomination for Best Supporting Actor for his role as the mentally disabled Rory in Square Dance (1987).

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