Tyrosine kinase inhibitors are a type of targeted cancer medicine that can attack specific types of cancer cells and prevent them from multiplying. Although these inhibitors, called TKIs, can be very useful in fighting certain cancers, they also cause serious inflammatory side effects that limit their use. A Japanese research team has discovered the underlying mechanism that causes this inflammation. This study revealed the underlying mechanism by which the TKIs cause inflammation, and therefore provides the molecular basis that is essential to overcome the inflammatory-based side effects."
Atsushi Matsuzawa, Professor at the Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
The team's findings were published in The Journal of Immunology on February 6, 2023.
These TKIs are essential anticancer drugs. However, the use of TKIs frequently initiates inflammation in the body, such as the lung disease interstitial pneumonitis. From their earlier studies, the team had learned that a representative TKI called Gefitinib (GF) causes lung inflammation. GF is a helpful cancer medication used in treating certain breast, lung, and other cancers. It works by targeting the epidermal growth factor receptors. When the GF is used to treat the cancer, it can also cause inflammation in the patient's lungs, through the NLRP3 inflammasome. The NLRP3 inflammasome is part of the body's immune system and plays an important role in innate immunity. But when the NLRP3 inflammasome is improperly activated, it can contribute to the development of a wide range of inflammatory diseases.
Until now, scientists have not fully understood why the NLRP3 inflammasome is activated, but the evidence seems to point to mitochondrial dysfunction. When mitochondria are healthy, they work like batteries, producing energy in the body's cells. Mitochondrial dysfunction happens when the mitochondria do not work as they should because of disease. In their earlier study, the team learned that the GF activated the NLRP3 inflammasome through mitochondrial damage that led to the interstitial pneumonitis in patients. However, they had not understood how GF initiates the mitochondrial damage and whether or not other TKIs also shared this mechanism. Cancer Research eBook Compilation of the top interviews, articles, and news in the last year. Download a free copy
To conduct their study, the team looked at the tyrosine kinases, those enzymes that work as a kind of "on" and "off" switch in many of the cells' functions. They specifically studied the Src family kinases, called SFKs. The SFKs are nonreceptor tyrosine kinases that regulate many cell processes. There are 11 types of SFKs in the human genome. Some of these SFKs are in the mitochondria and they play an essential role in the function of the mitochondria. The team found that all the TKIs they tested inhibit the kinase activity of the SKFs in the mitochondria which is responsible for the NLRP3 inflammasome.
The team's comprehensive analysis of the TKIs they tested revealed that these TKIs act as powerful agonists. In addition, the team observed off-target activity that could contribute to the side effects. "As an important finding, all TKIs we tested share a common off-target activity against the mitochondrial SFKs. Therefore, blocking the access of TKIs to mitochondria is a good way to prevent the inflammation," said Matsuzawa. They also noted that the other TKIs that do not affect the activity of the mitochondrial SFKs may overcome the inflammatory-based side effects. As another approach, when effective inhibitors of the NLRP3 inflammasome are developed, administering the TKIs at the same time as the NLRP3 inhibitors can counteract the side effects. The team's results provide insight into both the biological and the clinical significance of the NLRP3 inflammasome and the SFKs.
Looking ahead, the team's next step is to propose a new approach to avoid the inflammatory-based side effects of TKIs. They hope to lead in the development of new TKIs that do not initiate inflammation.
The research team includes Yuto Sekiguchi, Saya Takano, Takuya Noguchi, Tomohiro Kagi, Ryuto Komatsu, Maoko Tan, Yusuke Hirata, and Atsushi Matsuzawa from the Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan. Source:
Tohoku UniversityJournal reference:
Sekiguchi, Y., et al. (2023) The NLRP3 inflammasome works as a sensor for detecting hypoactivity of the mitochondrial Src family kinases. The Journal of Immunology. doi.org/10.4049/jimmunol.2200611.
College football reporter; joined ESPN in 2008. Graduate of Northwestern University.
While Dabo Swinney isn’t inflating LSU‘s grade for beating his team in Saturday’s season opener, Brian Kelly is ready to give the Clemson coach an incomplete for his evaluation.
Both coaches weighed in Tuesday on how LSU’s 17-10 win at Clemson should be viewed. After trailing 10-3 at halftime, LSU outscored Clemson 14-0 in the second half and finished with significant edges in both total yards (354-261) and first downs (25-13).
LSU rose six spots to No. 3 in the AP Top 25 poll Tuesday, while Clemson dropped four spots to No. 8.
“It was a helluva game, down to the last play,” Swinney said in his weekly news conference. “Right out of the gate. It’s like getting the final exam [on] Day 1 of class. They made a 65; we made a 58. Neither one of us were great.”
Kelly had not won a season opener at LSU before Saturday, and the victory was his first with the Tigers against an AP top-5 opponent.
“I thought we dominated them in the second half, so he’s really a really good grader for giving himself a 58, or he’s a really hard grader on us,” Kelly said in his news conference when told about Swinney’s comment.
“Or he didn’t see the second half, which, that might be the case. He might not have wanted to see the second half.”
Kelly added that LSU is moving on to this week’s game against Louisiana Tech.
“Clemson is a darn good football team,” Kelly said. “That’s a top-notch team, and they’re going to be a team in the hunt for [the] playoff picture. We hope we are, too. But it was only one game. So I don’t know if he’s a hard grader or an easy grader, but I like the way that we played in the second half.”
Ohio State climbed to No. 1 in the Associated Press Top 25 college football poll on Tuesday, LSU and Miami moved into the top five, and Florida State jumped back into the rankings at the expense of Alabama, which plummeted to its lowest spot in 17 seasons.
The defending national champion Buckeyes received 55 of 66 first-place votes to move up two spots after their win over preseason No. 1Texas. Ohio State is at the top of a regular-season poll for the first time since November 2015.
The Longhorns dropped to No. 7 as the media voters shuffled the rankings following a topsy-turvy Labor Day weekend. It was only the second time — and first since 1972 — that two top-five teams lost in Week 1 and the first time that four top-10 teams lost.
Only three teams in the Top 25 are in the same spot they were in the preseason poll.
Penn State got seven first-place votes and remained No. 2. LSU, which received three first first-place votes, was followed by Georgia and Miami to round out the top five.
The biggest movers in the poll were Florida State and Alabama after the Seminoles’ 31-17 victory in their head-to-head matchup.
The Seminoles, who were 15 spots outside the Top 25 in the preseason, are now No. 14. The Crimson Tide fell all the way from No. 8 to No. 21 — their lowest ranking since Bama was No. 24 in the 2008 preseason poll. That was the second of Nick Saban’s 17 teams in Tuscaloosa.
It’s been quite a turnabout for Florida State. The Seminoles were No. 10 in the 2024 preseason, lost their first two games, finished 2-10 and weren’t ranked again until now.
Utah, at No. 25, joins Florida State as the only newcomers to this week’s poll. The Utes are ranked for the first time since last October, when they were at the front end of a seven-game losing streak.
Utah had received the second-most points, behind BYU, among teams outside the preseason Top 25, but the Utes got more credit for beatingUCLA on the road than the Cougars received for hammering FCS foe Portland State.
Boise State, which had been No. 25, received no votes following its 34-7 loss at South Florida. The Broncos had appeared in 14 straight polls.
Ohio State is the first team to take over the top spot in the first regular-season poll since Alabama in 2012. It was the biggest jump to No. 1 in the first regular-season poll since USC was promoted from No. 3 in 2008.
Texas’ fall was the biggest for a preseason No. 1 since Auburn dropped to No. 8 in the first regular-season poll of 1984.
LSU has its highest ranking after Week 1 since it was No. 3 in 2012, and Miami has its highest ranking after Week 1 since it was No. 5 in 2004.
South Carolina is in the top 10 in the regular season for the first time since it was No. 8 in December 2013.
No. 15 Michigan at No. 18 Oklahoma: This weekend’s game will be the first meeting since Oklahoma beat the Wolverines in the Orange Bowl to win the 1975 national championship. Wolverines freshman QB Bryce Underwood gets put to the test in his second start.
Eli Lederman covers college football and recruiting for ESPN.com. He joined ESPN in 2024 after covering the University of Oklahoma for Sellout Crowd and the Tulsa World.
Oklahoma coach Brent Venables said Bryce Underwood “looks to be wise beyond his years” and compared Michigan‘s freshman quarterback to former Clemson national championship QB Trevor Lawrence on Tuesday ahead of the No. 18 Sooners’ Week 2 visit from the No. 15 Wolverines.
Underwood, ESPN’s No. 1 overall recruit in the 2025 class, will make his second career start at Oklahoma on Saturday (7:30 p.m. ET, ABC).
The coveted freshman earned Michigan’s starting job at the end of fall camp, beating out a collection of experienced passers on the depth chart including offseason portal additions Mikey Keene (Fresno State) and Jake Garcia (East Carolina). Underwood delivered a smooth college debut against New Mexico in Week 1, completing 21 of 31 passes for 251 yards and a touchdown in Michigan’s 34-17 win.
At Oklahoma, Underwood is set to face a much stiffer challenge against Venables, who resumed control of the Sooners’ defensive playcalling ahead of the 2024 season, and an experienced defense that held Illinois State to 151 yards of total offense in Week 1.
The former Clemson defensive coordinator compared Underwood to Lawrence, the five-star quarterback prospect who started as a freshman in 2018 and led the Tigers to a national championship win over Alabama.
“He’s a little different,” Venables said of Underwood. “It reminds me a lot of a Trevor Lawrence. Quick. Decisive. Accurate. Poised. Tough. Consistent. There’s a reason he was the No. 1 player in America. And he’s got a maturity and a work ethic and leadership agility to go along with that.”
As Oklahoma seeks to rebound from a 6-7 finish last fall, a new-look Sooners offense will get a test of its own Saturday.
Behind transfer QB John Mateer and first-year offensive coordinator Ben Arbuckle, Oklahoma gained 495 yards of offense in its 35-3, season-opening win over Illinois State. Mateer, who arrived in the offseason from Washington State alongside Arbuckle, passed Baker Mayfield for the most passing yards by an Oklahoma QB in a debut with 392 yards.
On Tuesday, Venables highlighted the Wolverines’ experience on defense, particularly in the front seven, as a defining challenge for the Sooners in an intriguing Week 2 matchup between two of college football’s most storied brands.
“[It’s] a defense that for the last several years has been one of the gold standards of college football when it comes to playing good defense,” Venables said. “It’s going to be a great physical matchup, and for us, a great litmus test to where we’re at.”