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Biological importance of Gab1 in HNSCC cells

Preclinical and clinical studies have evidenced that effective targeted therapy treatment designed against receptor tyrosine kinases (RTKs) in different solid tumor paradigms is predicated on simultaneous inhibition of both the PI3K and MEK intracellular signaling pathways. Indeed, reactivation of either pathway results in resistance to these therapies. Recently, oncogenic phosphatase SHP2 inhibitors have been developed with some now reaching clinical trials. To expand on possible indications for SHP099, we screened over 800 cancer cell lines covering over 25 subsets of cancer. We found head and neck squamous cell carcinoma (HNSCC) was the most sensitive adult subtype of cancer to SHP099. We found that, in addition to the MEK pathway, SHP2 inhibition blocks the PI3K pathway in sensitive HNSCCs, resulting in downregulation of mTORC signaling and antitumor effects across several HNSCC mouse models, including an human papillomavirus (HPV+) patient-derived xenograft. Importantly, we found low levels of the RTK ligand epiregulin identified HNSCCs that were sensitive to SHP2 inhibitor, and, adding exogenous epiregulin mitigated SHP099 efficacy. Mechanistically, epiregulin maintained SHP2–GAB1 complexes in the presence of SHP2 inhibition, preventing downregulation of the MEK and PI3K pathways. In the presence of SHP2 inhibitor, HNSCCs are highly dependent on GAB1 for their survival and knockdown of GAB1 is sufficient to block the ability of epiregulin to rescue MEK and PI3K signaling. These data connect the sensitivity of HNSCC to SHP2 inhibitors and to a broad reliance on GAB1-SHP2, revealing an important and druggable signaling axis. Overall, SHP2 inhibitors are being heavily developed and may have activity in HNSCCs, and in particular those with low levels of epiregulin.Significance:This work identifies a novel role of SHP2 inhibitor by dual downregulation of PI3K and MEK pathways, through loss of GAB1 activation and disruption of GAB1 complexes in low-epiregulin HNSCC.

Cell line information and SHP099 screen data

Preclinical and clinical studies have evidenced that effective targeted therapy treatment designed against receptor tyrosine kinases (RTKs) in different solid tumor paradigms is predicated on simultaneous inhibition of both the PI3K and MEK intracellular signaling pathways. Indeed, reactivation of either pathway results in resistance to these therapies. Recently, oncogenic phosphatase SHP2 inhibitors have been developed with some now reaching clinical trials. To expand on possible indications for SHP099, we screened over 800 cancer cell lines covering over 25 subsets of cancer. We found head and neck squamous cell carcinoma (HNSCC) was the most sensitive adult subtype of cancer to SHP099. We found that, in addition to the MEK pathway, SHP2 inhibition blocks the PI3K pathway in sensitive HNSCCs, resulting in downregulation of mTORC signaling and antitumor effects across several HNSCC mouse models, including an human papillomavirus (HPV+) patient-derived xenograft. Importantly, we found low levels of the RTK ligand epiregulin identified HNSCCs that were sensitive to SHP2 inhibitor, and, adding exogenous epiregulin mitigated SHP099 efficacy. Mechanistically, epiregulin maintained SHP2–GAB1 complexes in the presence of SHP2 inhibition, preventing downregulation of the MEK and PI3K pathways. In the presence of SHP2 inhibitor, HNSCCs are highly dependent on GAB1 for their survival and knockdown of GAB1 is sufficient to block the ability of epiregulin to rescue MEK and PI3K signaling. These data connect the sensitivity of HNSCC to SHP2 inhibitors and to a broad reliance on GAB1-SHP2, revealing an important and druggable signaling axis. Overall, SHP2 inhibitors are being heavily developed and may have activity in HNSCCs, and in particular those with low levels of epiregulin. Significance: This work identifies a novel role of SHP2 inhibitor by dual downregulation of PI3K and MEK pathways, through loss of GAB1 activation and disruption of GAB1 complexes in low-epiregulin HNSCC.

Triple negative breast cancer (TNBC) accounts for over 30% of all breast cancer (BC)-related deaths, despite accounting for only 10% to 15% of total BC cases. Targeted therapy development has largely stalled in TNBC, underlined by a lack of traditionally druggable addictions like receptor tyrosine kinases (RTKs). Here, through full genome CRISPR/Cas9 screening of TNBC models, we have uncovered the sensitivity of TNBCs to the depletion of the ubiquitin-like modifier activating enzyme 1 (UBA1). Targeting UBA1 with the first-in-class UBA1 inhibitor TAK-243 induced unresolvable endoplasmic reticulum (ER)-stress and activating transcription factor 4 (ATF4)-mediated upregulation of proapoptotic NOXA, leading to cell death. c-MYC expression correlates with TAK-243 sensitivity and cooperates with TAK-243 to induce a stress response and cell death. Importantly, there was an order of magnitude greater sensitivity of TNBC lines to TAK-243 compared to normal tissue-derived cells. In five patient derived xenograft models (PDXs) of TNBC, TAK-243 therapy led to tumor inhibition or frank tumor regression. Moreover, in an intracardiac metastatic model of TNBC, TAK-243 markedly reduced metastatic burden, indicating UBA1 is a potential new target in TNBC expressing high levels of c-MYC.

Triple negative breast cancer (TNBC) accounts for over 30% of all breast cancer-related deaths, despite accounting for only 10%–15% of total breast cancer cases. Targeted therapy development has largely stalled in TNBC, underlined by a lack of traditionally druggable addictions like receptor tyrosine kinases (RTKs). Here, through full genome CRISPR/Cas9 screening of TNBC models, we have uncovered the sensitivity of TNBCs to the depletion of the Ubiquitin-Like Modifier Activating Enzyme 1 (UBA1). Targeting UBA1 with the first in-class UBA1 inhibitor TAK-243 induced unresolvable ER-stress and activating transcription factor 4 (ATF4)-mediated upregulation of pro-apoptotic NOXA, leading to cell death. In five patient derived xenograft models (PDXs) of TNBC, TAK-243 therapy led to tumor inhibition or frank tumor regression. In an intracardiac metastatic model of TNBC, TAK-243 markedly reduced metastatic burden. Importantly, there was an order of magnitude greater sensitivity of TNBC lines to TAK-243 compared to normal tissue-derived cells. Lastly, c-MYC expression correlates with TAK-243 sensitivity and cooperates with TAK-243 to induce a stress response and cell death. We posit UBA1 is an important new target in TNBC expressing high levels of c-MYC.SignificanceGenomic screening of TNBC cell lines revealed broad sensitivity to depletion of the E1 ubiquitin enzyme, UBA1. Disrupting UBA1 with the first in-class inhibitor TAK-243 in TNBC models induces ER-stress through an ATF4-NOXA axis that is dependent on c-MYC, leading to apoptosis, in vitro and in vivo, primary tumor growth inhibition and metastatic inhibition.

To characterize outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19) who present with gastrointestinal (GI) symptoms.Clinical outcomes in patients with COVID-19 associated with GI symptoms have been inconsistent in the literature.The study design is a retrospective analysis of patients, age 18 years or older, admitted to the hospital after testing positive for COVID-19. Clinical outcomes included intensive care unit requirements, rates of discharges to home, rates of discharges to outside facilities, and mortality.Seven hundred fifty patients met the inclusion criteria. Three hundred seventy three (49.7%) patients presented with at least one GI symptom and 377 (50.3%) patients presented with solely non-GI symptoms. Patients who presented with at least one GI symptom had significantly lower ICU requirements (17.4% vs 20.2%), higher rates of discharges home (77.2% vs 67.4%), lower rates of discharges to other facilities (16.4% vs 22.8%), and decreased mortality (6.4% vs 9.8%) compared with patients with non-GI symptoms. However, patients who presented with solely GI symptoms had significantly higher ICU requirements (23.8% vs 17.0%), lower rates of discharges home (52.4% vs 78.7%), higher rates of discharges to facilities (28.6% vs 15.6%), and higher mortality (19.0% vs 5.7%) compared with those with mixed GI and non-GI symptoms.Although patients with COVID-19 requiring hospitalization with GI symptoms did better than those without GI symptoms, those with isolated GI symptoms without extra-GI symptoms had worse clinical outcomes. COVID-19 should be considered in patients who present with new onset or worsening diarrhea, nausea, vomiting, and abdominal pain even without pulmonary symptoms.

Ferroptosis is an iron-dependent, oxidative form of cell death that is countered mainly by glutathione peroxidase 4 (GPX4) and the production of glutathione (GSH), which is formed from cysteine. The identification of the cancers that may benefit from pharmacological ferroptotic induction is just emerging. We recently demonstrated that inducing ferroptosis genetically or pharmacologically in