BCL2L1 mutation

This report provides the first detailed description of the FNA cytology of LCNEC/SCC, thereby enhancing cytopathologists' comprehension of this tumor. Auxiliary studies, including ICC staining and molecular biology assays, are crucial for accurate diagnosis, therapy, and prognosis.

CDK4 high-level copy number increase coexists with other pathogenic mutations in AM. CDK4 appears to be a promising target for AM treatment and is expected to be combined with other targeted therapies.

Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.

Leukemia drug venetoclax is currently the only approved selective BCL-2 inhibitor...Furthermore, we identify a single-residue discrepancy between BCL-2 D111 and BCL-XL A104 as a molecular "switch" that can differently engage CPs. Our study suggests that CPs may inhibit BCL-2 or BCL-XL by delicately modulating protein-protein interactions, potentially benefiting the development of next-generation therapeutics.

Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.

Venetoclax is a specific inhibitor of Bcl-2, the key protein which protects CLL cells from intrinsic apoptosis, whereas the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib kills CLL cells via blockade of B-cell receptor (BCR) signalling. In conclusion, WH25244 is a PROTAC-based Bcl-2/Bcl-xL degrader with the potential to overcome venetoclax-resistant CLL dependent on Bcl-xL and mutant Bcl-2. Relative to its precursor, navitoclax, it shows increased potency against CLL cells and decreased toxicity against platelets in vitro, due to its VHL-dependent activity and minimal expression of VHL in platelets.

Despite study limitations (mainly the small cohort), this preliminary data suggests that the expression levels of BCL2 family proteins may represent a predictor of response to RUX. Specifically, we developed a simple, combinatorial score including baseline BCL-2 and BCL2L1 expression that accurately discriminated pts who responded to RUX. Moreover, we showed that BCL2 family protein expression changes during RUX treatment, with potential correlations with both response achievement and loss.

To evaluate if combination treatment of AZD0466 with BTK inhibitors would improve efficacy, we transplanted murine Eµ-TCL1 tumors into syngeneic recipient mice and randomized them for treatment with vehicle, ibrutinib (30mg/kg in drinking water), acalabrutinib (25mg/kg, p.o. QD), AZD0466 (70mg/kg, i.v., QW) and combination of AZD0466 with ibrutinib or acalabrutinib. Moreover, AZD4320 was highly efficacious in MAVER-1 and MINO cell line models where resistance to venetoclax mediated by BCL-XL upregulation was modelled by an in vitro dose escalation method. In summary, our pre-clinical study shows that the dual BCL2/BCL-XL inhibitor could represent an important treatment option for venetoclax resistance mediated by specific BCL2 mutations or BCL-XL upregulation and that its efficacy could be further improved upon combination treatment with BTKi.

Knowing that BCL-xL inhibition in the clinic has been limited by platelet toxicity, PROTACs PZ18753b and WH25244 were synthesized from navitoclax (BCL-2/BCL-xL dual inhibitor) linked to a VHL E3 ligase ligand to target Bcl-2 and Bcl-xL for degradation, with improved specificity to cancer cells while sparing platelets. PZ18753b and WH25244 have preclinical efficacy in baseline CLL and can degrade, both, Bcl-xL and mutant Bcl-2 proteins, which are known to confer venetoclax resistance. This translational study supports the development of novel therapeutics for the treatment of CLL subgroups with adverse clinical prognosis and will open new frontiers as we better understand the biology of this disease.

Conclusions Navitoclax in combination with trametinib was tolerable, and the R2PD was established. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation of combined BCL-XL/MEK inhibition in this population.

In particular, we focused on ATM/ATR involved in DNA damage response (DDR); PKM2, PDK1, LDH-A and complex I of OXPHOS involved in energy metabolism and Bcl-2/Bcl-xL involved in antiapoptotic processes.Material and MethodsH1993, H1975 and A549 oncogene-driven NSCLC cells were treated with TKIs (crizotinib, osimertinib or erlotinib) and in parallel with a combination of two of selected NOA inhibitors (DCA, benserazide, oxamate, IACS-10759, KU55933, M4344 and ABT-263). Finally, PDKs inhibition with DCA caused a significant dose-dependent decrease of glucose consumption and increase of OXPHOS subunits.ConclusionOur preliminary data suggest that targeting these proteins may destabilize tumor environment thus coupling metabolic phenotype and DDR to drug resistance. The major translational relevance of this study is to exploit these new targets for innovative and improved therapeutic strategies in comparison to TKI therapies in NSCLC patients.

After the first induction cycle with the 7+3 scheme (cytarabine + idarubicin), refractoriness was observed, in addition to the appearance of 6% of nuclei with BCL2 amplification by FISH, while maintaining the TP53 variant (confirmed by PCR). A new therapeutic scheme was initiated with decitabine 10- venetoclax... Clonal evolution of the leukemia was evidenced by the acquisition of BCL2 amplification alongside changes in the karyotype after antineoplastic treatment, and particularly following venetoclax administration, while maintaining the primary TP53 pathogenic variant.The increasing use of targeted therapies is improving remission and survival rates in most hematologic neoplasms, but it is also leading to the emergence of therapy-related clonal selections, as seen in this case, which could cause resistant relapses or even refractoriness. Understanding the mechanisms responsible for these phenomena would help to understand their relevance in the evolution of these patients.