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Reviewed by Emily Henderson, B.Sc. Mar 17 2023

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.

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Horns’ Ewers leads ‘new era’ of college football

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Horns' Ewers leads 'new era' of college football

ARLINGTON, Texas — Texas coach Steve Sarkisian said Thursday that quarterback Quinn Ewers, with the emergence of name, image and likeness and the transfer portal, has become the face of this “new era of college football.”

Ewers initially committed to Texas, but he then opted to skip his senior year of high school and reclassify to the 2021 recruiting class before enrolling a year early and joining Ohio State during preseason practice.

Still the nation’s No. 1 ranked overall prospect, Ewers landed one of the first marquee NIL deals worth $1.4 million.

Ewers, who lasted one season with the Buckeyes before transferring to Texas, will square off against Ohio State on Friday night in the Goodyear Cotton Bowl with a trip to the College Football Playoff national championship on the line.

“It’s not been an easy journey for him,” Sarkisian said Thursday. “There’s been ups, there’s been downs, there’s been injuries, there’s been great moments, there’s been tough moments. … But at the end of the day, he’s always stayed true to who he is. The guy’s been a steady sea for us.”

Ewers has been making college football headlines since Ohio State offered him a scholarship when he was just in middle school. This week, Buckeyes coach Ryan Day recalled meeting Ewers for the first time when he was an eighth-grader visiting a Buckeyes football camp.

“He was a boy at the time really, who just had a tremendous release,” Day recalled. “And I remember grabbing him and grabbing his dad and said, ‘Man, you got a bright future ahead of you. I don’t know if this is good or bad, but we’re going to offer you a scholarship to Ohio State.'”

C.J. Stroud, who has since led the Houston Texans to the NFL playoffs, emerged as a star quarterback for the Buckeyes then, prompting Ewers to transfer to Texas.

“Boy, it was strange how it all shook out,” Day said. “He decided he really wanted to play. And it was disappointing for us, but we certainly understood. From afar I’ve watched him. He’s a really good player. He comes from a great family, and he’s had a great career at Texas and a lot of people here still have good relationships with him and think the world of him.”

At Texas, Ewers has started in 27 wins and led the Longhorns to back-to-back playoff appearances. This season, he has thrown for 3,189 yards and 29 touchdowns with 11 interceptions.

Ewers noted that the “coolest part” of the NIL era is being able to provide for his parents. He has even hired his mom, making her CFO of his finances while giving her a salary.

“Which is nice just because all the effort and work they put into me growing up,” he said. “I mean, when we were living in South Texas, they both quit their jobs and moved up to Southlake [to support Ewers’ budding athletic career].”

Whatever happens in the playoff — whether it be a loss Friday or a national championship victory against the winner of Notre DamePenn State on Jan. 20 — Ewers’ career at Texas figures to be coming to a close.

Though Ewers still has one season of eligibility remaining, blue-chip quarterback prospect Arch Manning appears primed to finally take over in Austin next season.

Manning, the nephew of NFL quarterback greats Peyton and Eli Manning, who could become the No. 1 overall prospect for the 2026 NFL draft, has backed up Ewers for two seasons waiting for his opportunity. Sarkisian even momentarily benched Ewers in favor of Manning during Texas’ 30-15 loss to Georgia on Oct. 19.

Still, Ewers figures to have options.

ESPN football analyst Mel Kiper Jr. ranks him as the No. 6 quarterback prospect eligible for the upcoming draft. Rumors have also emerged recently that Ewers could put off the NFL for another year and transfer to a third school for millions more in NIL money.

Amid those distractions, Ewers has thrived in the playoff bouncing back from oblique and ankle injuries from earlier in the year to complete 69% of his passes with four touchdowns in Texas’ two victories.

In the Chick-fil-A Peach Bowl quarterfinal, Ewers tossed 29- and 25-yard touchdown passes in the overtimes, lifting Texas to the 39-31 win over Arizona State.

“I’ve just been proud of him,” Sarkisian said, “because he’s found a source for him that has been a motivating factor, where he can play free and play loose and play confident.”

Ewers added that, whatever the future holds, even contemplating it now would be “selfish,” with a national title still in reach for him and the Longhorns.

“I owe my teammates the best version of me right now,” he said. “I can’t be looking forward or I’ll trip on the rock that’s sitting right in front of me. I’ve got to be locked in on what’s right here.”

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Texas RT Williams back in lineup for CFP semi

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Texas RT Williams back in lineup for CFP semi

ARLINGTON, Texas — Texas starting right tackle Cameron Williams will return for the College Football Playoff semifinal against Ohio State on Friday, Longhorns coach Steve Sarkisian said Thursday.

Williams suffered a right knee sprain in the playoff opener against Clemson. The injury forced him to miss Texas’ quarterfinal overtime victory over Arizona State.

A junior, Williams has played in 37 games in his career with 16 starts for the Longhorns. Williams is rated as the No. 28 overall prospect and fifth offensive tackle in ESPN’s NFL draft rankings.

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Sources: Georgia QB Beck enters transfer portal

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Sources: Georgia QB Beck enters transfer portal

Georgia quarterback Carson Beck has entered the NCAA transfer portal, sources confirmed to ESPN on Thursday.

Beck had declared for the NFL draft on Dec. 28 but is now reversing course and will explore a transfer.

Sources told ESPN that Miami looms as the favorite for Beck and the timeline for his decision is expected to play out within a week.

While Miami is the favorite for Beck, a source said Beck’s camp intends to listen to all potential suitors for the best situation: “It’s a strategic thing, not an emotional thing,” the source said.

Beck, a two-year starter at Georgia, is currently recovering from surgery to repair the ulnar collateral ligament in his throwing elbow after suffering the injury during the Bulldogs’ SEC championship victory over Texas.

Beck will not be able to throw until March, sources told ESPN, which would have complicated his NFL draft process and will likely force him to miss spring practice at his next school. Sources said the variety of feedback he got from the draft process led to this decision, as he changed his mind in the past 24 hours. He received advice that if he could return and wanted to, he should probably return and play another season in college.

A source said Beck received feedback that he could end up anywhere between the first and third round, with much of that uncertainty due to the fact that he would not be able to throw for a team in predraft workouts.

Despite that injury setback, Beck will immediately become the most coveted quarterback available as a late entry to the transfer market. While Miami looms as the favorite, there are other big brand teams that could jump out as suitors including Texas Tech and Notre Dame.

The 6-foot-4, 220-pound senior went 24-3 as the Bulldogs’ starter and was viewed as a potential No. 1 draft pick entering the 2024 season. He threw for 3,485 yards with 28 touchdowns and 12 interceptions this season and led Georgia back to the SEC title game.

Beck injured his elbow on the final play of the first half against Texas on Dec. 7. Renowned orthopedic surgeon Dr. Neal ElAttrache performed Beck’s surgery on Dec. 23 in Los Angeles.

“He wants to win,” said the source close to Beck. “He didn’t come back to get knocked out at halftime of a conference championship.”

Entering his fifth college season, Beck was viewed as a potential top-10 draft pick. ESPN’s Mel Kiper Jr. currently considers Beck the No. 5 quarterback in his draft rankings.

Miami has not added a transfer quarterback this offseason to succeed Cam Ward, the potential No. 1 pick. They’ve quietly been canvassing the transfer market in recent weeks, per sources, as they have been set on bringing in a front-line starter who can produce immediately, much like Ward did.

Ward made a similar decision last January, initially declaring for the NFL draft but changing his mind and transferring to join the Hurricanes after he was unsatisfied with his draft feedback. Ward finished fourth in Heisman Trophy voting in his lone season in the program after producing 4,313 passing yards and 43 total touchdowns.

On3 first reported Beck’s intentions to enter the portal.

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