@operapadrepio

@operapadrepio

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Oggi vi parlo di cosa studiamo in laboratorio. Da oltre cinque anni in @operapadrepio con il team della dott.ssa Muscarella lavoriamo alle lesioni molecolari nel tumore polmonare di un gene chiamato #NRG1. Mi scuso in anticipo per alcuni tecnicismi che troverete. 1/18
#lungcancer

Intro. In particolar modo il focus è sulle fusioni geniche che interessano riarrangiamenti a carico delle Neureguline (NRG1-4) recentemente descritti nel carcinoma polmonare non a piccole cellule (NSCLC). Ma andiamo per ordine, partendo dalle basi. 2/18

Le basi/1. Per fusione genica si intende un’alterazione in cui due geni si fondono andando a formare un gene “anomalo”, il più delle volte originatosi dalla prima metà di un gene e dalla seconda metà del secondo. 3/18

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Stephen V Liu

@StephenVLiu

@TakashiKohno2

#WCLC20 Summary of molecular epidemiology of Asian lung cancer at the opening plenary by @TakashiKohno2. There are many different genomic subtypes of lung cancer and huge geographic variation. Reminder though: phenotype does not guide testing. #LCSM @OncoAlert

@OncoAlert

#WCLC20 In the US, actionable genomic alterations more common in never-smokers but still occur at relevant rates in smokers (and smokers probably undertested). In Japan, very high rates of alterations (like EGFR) in both smokers and never-smokers. #LCSM @OncoAlert

#WCLC20 But why? Why are there so many cases of lung cancer in never-smokers in Asia? Unique exposures? HLA differences? Why adeno and not squamous? Important work that will impact screening and treatment but very early. Is there a similar link with Native American ancestry?

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Stephen V Liu

@StephenVLiu

@OncoAlert

#ESMO20 Happy to share the first results of RAIN-701, a phase II study of #tarloxotinib in patients with NSCLC harboring an #EGFR exon 20 insertion or an activating #HER2 mutation and any solid tumor with an #NRG1 or ERBB gene fusion. #LCSM @OncoAlert

@OncoAlert

#ESMO20 Tarlox is given as an inactive prodrug that embeds in the cell membrane. Only when it encounters hypoxia does it undergo single electron reduction to fragment to a cell permeable, pan-HER, irreversible TKI with subnanomolar potency at EGFR, HER2 and HER4. @OncoAlert #LCSM

#ESMO20 Top right shows the IC50 of Tarloxotinib-E in human cell lines, bottom right corroborate with additional mutations in BAF3 models. Note the differential target inhibition for Tarlox-E with a lower IC50 for #HER2 than EGFR and the lowest IC50 for #NRG1 fusions. #LCSM

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Stephen V Liu

@StephenVLiu

@CCR_AACR

#OncoAlert Important paper now online @CCR_AACR by Dr. Dagogo-Jack @JessicaJLinMD @JustinGainor @MGHThoracicOnc on #MET alterations mediating acquired resistance to #ALK TKI therapy in #NSCLC. Analysis of > 200 post-treatment specimens by FISH/NGS. #LCSM

clincancerres.aacrjournals.org/content/early/…

#MET amplification was seen in 12% of patients post 2nd-gen #ALK TKI and 22% of patients post-lorlatinib. With first line alectinib and brigatinib, MET amplification seems more likely (logical given activity of crizotinib at MET). MET rearrangements also identified! #LCSM

As we have several #MET kinase inhibitors (including crizotinib), combinations may overcome resistance (could they prevent it?). In the setting of targeted therapy for #NSCLC, molecular testing at progression increasingly relevant (tissue, plasma - I would favor both). #LCSM

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Stephen V Liu

@StephenVLiu

@alexdrilon

#DCLUNG19 Daunting task of all non-EGFR/ALK drivers in #NSCLC handled easily by @alexdrilon - in #ROS1, note that not all ALK inhibitors are ROS1 inhibitors. Variation in CNS activity. Many active drugs to consider. #LCSM #LCAM

@alexdrilon

#DCLUNG19 Highly active, CNS penetrant and well tolerated TKIs for #RET and #NTRK fusion positive cancers, outlined by expert @alexdrilon

#DCLUNG19 Dabrafenib and trametinib active in #BRAF but be sure it’s V600E! Three drugs with breakthrough designation for #METex14. HER2 is a target but not copy number for #NSCLC, its mutations (usually ex20). #LCSM #LCAM

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Stephen V Liu

@StephenVLiu

@rdoebele

#WCLC19 @rdoebele kicks off the plenary with a discussion of tumor agnostic therapy. Really refers to biology driven. Our current siloed approach to oncology is a bit of a barrier to this strategy. Timing favored lung cancer as the field where this became mainstream. #OncoAlert

#NTRK is a great example where we see efficacy across tumors and no indication of a specific tumor type resistant to inhibition. But we see similar themes in #ALK and #ROS1 - will there be a regulatory path forward? #OncoAlert #WCLC19

Importantly, resistance also seems to be tumor agnostic. Similar mutations seen mediating resistance across tumor types. Predicting #NRG1 as next important target across tumor types. Biology is more dependent on the genomics than the histology! #WCLC19 #OncoAlert

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Stephen V Liu

@StephenVLiu

@RymaBenayed

#OncoAlert Important work by @RymaBenayed @MLadanyi in @CCR_AACR online now reviewing why RNA testing is critical for patients with #NSCLC in the important search for actionable driver alterations to guide proper therapy #LCSM

clincancerres.aacrjournals.org/content/early/…

@RymaBenayed

@RymaBenayed @MLadanyi @CCR_AACR #OncoAlert The authors analyzed 254 patients with lung adenocarcinoma who were driver negative by MSK-IMPACT (DNA based NGS) and had enough tissue for RNA sequencing with ARCHER. 232 successfully sequenced and they identified 36 driver events or 15.5% of these patients! #LCSM

@RymaBenayed

@RymaBenayed @MLadanyi @CCR_AACR The most common were #ROS1 (28%), #NRG1 (14%), #ALK (11%), #RET (8%) and #NTRK (8%). Patients able to receive targeted therapy had the expected good outcomes. @ros1cancer @EGFRResisters @ALKLungCancer

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