New paper from @SimpsonLabUW @DermatologyUW is online @JCI_insight🍾We found ERK hyperactivation disrupts cell-cell adhesion in epidermis, linked this pathway to both drug-induced & spontaneous Grover disease & identified MEK inhibition as a novel therapy:

Excited to be representing @SimpsonLabUW in sunny 😎 San Diego 🌴 for #ASCB2024 #CellBio2024 @ASCBiology

Starting the migration to the other place, using handle @SimpsonLabUW …hoping to find the old #sciencetwitter and #dermtwitter crowds.

Proud of med student Rafael Homer whose summer research project @SimpsonLabUW @DermatologyUW won 2nd place in the @uwsomwwami Wyoming site poster competition! Rafael also won a travel award to attend the Western Medical Research Conference & was chosen for an oral presentation🤩

Exciting week @SimpsonLabUW @DermatologyUW celebrating🍾our newest paper @JCI_insight (see separate🧵). which uncovered a mechanism that drives the pathology #Grover disease and was reversed using MEK inhibitors. Special thanks to Arti for making an amazing Indian lunch buffet!

Hope this will finally move the needle for severe drug reactions like SJS & TEN, nightmare consults in #dermatology. No Rx has great evidence to halt skin/mucosal sloughing that can be fatal. JAKi remains to be rigorously tested in patients/RCT but could change standard of care.

RT @Nature: Nature research paper: Spatial proteomics identifies JAKi as treatment for a lethal skin disease

This program has been an outstanding opportunity for networking with peers, receiving grant feedback, learning how to navigate the new PI path, and getting sage career advice from leading physician-scientists. 10/10 highly recommend @the_asci. Consider applying.

Proud of all co-authors & grateful to our collaborators @umichmedicine & @PennSbdrc including @drdremchu. Thanks to @NIH_NIAMS & @FIRST_Skin for lab support and @LEOFondet for funding my effort to find shared mechanisms & treatment strategies for rare skin #blistering diseases.

Finally, we reasoned the same mechanism could drive spontaneous Grover disease (ie, not drug-induced). Accordingly, we found ERK hyper-activation in Grover disease lesions and propose MEK inhibitors may be therapeutic for this idiopathic disorder lacking any FDA-approved therapy.

In fact, we found multiple different MEK inhibitors restored cell-cell adhesion despite B-RAF blockade. This was consistent with subsequent clinical trial data in which patients treated w/DUAL inhibitors of both B-RAF and MEK no longer got Grover disease as a side effect.

In keratinocytes, we showed ERK hyperactivation was sufficient to disrupt desmosomes & reduce cohesion, explaining why the epidermis falls apart in Grover disease. Importantly, blocking ERK activation w/an FDA-approved MEK inhibitor (trametinib) rescued keratinocyte cohesion.

We validated these findings in skin biopsies from patients who were treated w/vemurafenib and developed drug-induced Grover disease. These biopsies showed hyper-activation of ERK within lesional epidermis, which correlated with the disruption of cell-cell junctions (desmosomes).

We used a kinase reporter to show that the B-RAF inhibitors used in the clinical trials (dabrafenib/Dab or vemurafenib/Vem) induced paradoxical ACTIVATION of ERK in live human epidermal keratinocytes.

The story starts w/an unexpected side effect of B-RAF inhibitors seen in clinical trials for cancer. Some patients developed a skin blistering disorder called Grover disease, in which keratinocytes lose their connections to one another, leading to splitting of the epidermis.

RT @the_asci: Early-Faculty Physician-Scientists! . Nominations are open for the ASCI Young Physician-Scientist Awards. Award Benefits in….

Great lunch @SimpsonLabUW⁩ ⁦@DermatologyUW⁩ for lots of celebrating including Arti’s birthday 🥳 More good news to share soon now that I’m out from under the cloud of this R01 submission 😮‍💨📝 ✅🤞

RT @genehackrman: I'm excited to announce that I am on the job market for tenure-track Assistant Professor positions in cell biology, with….

Very proud of Akshata for representing @SimpsonLabUW @DermatologyUW at the @UWISCRM Fall Symposium. She did a great job at her 1st poster session explaining her work developing quantitative methods to assess our model of #HaileyHailey disease, a rare #skin #blistering disorder.

RT @HarrisTryonLab: Last day of Early Bird Registration! Can't wait to engage in transformative dialogue with skin scientist and clinician….