AXL Targeting Abrogates Autophagic Flux and Induces Immunogenic Cell Death in Drug-Resistant Cancer Cells

Abstract

Disclosure: Drs. Lorens and Micklem are founders, shareholders, and employees of BerGenBio ASA. Dr. Gausdal is employed by and stock option holder of BerGenBio ASA. Drs. Lorens, Micklem, Gausdal, Lotsberg, and Engelsen are co-inventors of patent(s) pending or issued to BerGenBio ASA. Drs. Wnuk-Lipinska and Hellesøy are former employees of BerGenBio ASA. Drs. Chouaib and Brekken signed Sponsored Research Agreements with BerGenBio ASA related to separate research projects. Dr. Bivona reports grants from National Institutes of Health during the conduct of the study; grants and other from Novartis, Revolution Medicines, personal fees from AstraZeneca, Takeda, Strategia, Springworks, Array, Pfizer, and Rain outside the submitted work. Dr. Minna reports grants from National Cancer Institute, Margot Johnson Foundation, and CPRIT during the conduct of the study, and personal fees from National Cancer Institute and University of Texas Southwestern Medical Center outside the submitted work. Dr. Thiery is the scientific founder of Biocheetah Pte. Ltd., Singapore and advisor of Biosyngen Pte. Ltd., Singapore. The remaining authors declare no conflict of interest.

Inhibition of pyruvate dehydrogenase kinase redirects NSCLC cell metabolism and counteracts development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors

“…The effects on E-cadherin and vimentin protein levels were supported by western blot analysis, and c-MET mRNA was reduced (Supplementary gure S4 B-C). This supports previous ndings for the H1975 model [85,86]. The mRNA expression of PDH subunits and the PDKs were evaluated in the resistant compared to the parental cells ( Fig.…”

“…The resistant sublines are referred to as HCC827/BERL and HCC4006/BERL. In addition, we used an established H1975 cell line, with a subline (H1975/COR1-1) resistant to the third generation EGFR TKI rociletinib (CO-1686), provided by Clovis oncology [85,86]. The H1975 cell line is known to be resistant towards erlotinib as they have a T790M mutation in EGFR exon 20, but sensitive towards rociletinib.…”

Autophagic flux inhibition enhances cytotoxicity of the receptor tyrosine kinase inhibitor ponatinib

“…The inhibition of autophagy by compounds already available, such as CQ and HCQ, could help in lowering the doses of PON required to affect tumor cell growth while improving its anti-neoplastic effects. These findings are of great relevance, since significant side effects have been reported in leukemia patients upon treatment with PON [ 45 ], and we may therefore need to decrease the concentration of such TKi in therapeutic protocols adopted for childhood malignancies, while maintaining their efficacy. One option could be an adjuvant therapy with CQ.…”

“…It is not rare for tumor cells to trigger autophagy in order to assure their survival after chemotherapy and radiotherapy treatments [ 44 ]. Autophagy-dependent mechanisms of acquired resistance to TKi that involve AXL signaling have recently been reported [ 45 ]; these mechanisms are activated after EGFR inhibition, upon which AXL takes over the transduction of the interrupted signaling. The cytoprotective role of AXL has been recognized in different tumor types [ 46 ], including non- MYCN –amplified neuroblastoma [ 47 ].…”

Bortezomib abrogates temozolomide-induced autophagic flux through an ATG5 dependent pathway

“…Cells were treated with BTZ 10nM for 48h, with and without CQ 50M for 24h. CYTO-ID Autophagy detection kit 2.0 (ENZ-KIT175-0050 , Enzo Life Sciences, Farmingdale, NY, USA) was used and to monitor the autophagic flux at the single-cell level as previously described61 and in accordance with manufacturer's instructions. The dynamic autophagosome generation and clearance was assessed by live cell flow cytometry using BD Accuri C6 flow cytometer (BD Biosciences).…”