Abstract Introduction: CHIC (Clonal Hematopoiesis In Lung Cancer) is a retro-prospective study that aims to describe the characteristics of clonal hematopoiesis (CH) in patients with non-small cell lung cancer (NSCLC). We present preliminary results from the retrospective cohort. Experimental procedures: A retrospective analysis conducted in patients with metastatic or recurrent NSCLC included in the MATCH-R study (NCT02517892) at Gustave Roussy (Villejuif, France). CH was evaluated by a 74-gene targeted NGS panel (HaloPlex - Agilent) performed on DNA extracted by isolated-by-blood leukocytes. The variant allele frequency (VAF) threshold of detection was set at 1%. Results: 108 consecutive patients with advanced NSCLC included from October 2015 to July 2019 were evaluated, irrespective of the tumor molecular profile. 46% of the patients were female, 67% were former or current smokers. 82% of the patients had adenocarcinoma and 44%, 23%, 33% had bone, liver and/or brain metastases, respectively. Patients had received a median of 2 lines of systemic therapy and 81% were on active anticancer treatment at the time of CH assessment. At least one CH mutation was found in 38 out of 108 patients (35% prevalence), with an increasing with age trend. Patients carrying CH were older as compared to those without CH and had in 29% vs. 11% of cases tumor histology other than adenocarcinoma (p=0.009). No difference in overall survival was observed according to CH detection (log rank p=0.318). We found 64 mutations in 19 different genes: 63% of the patients carried a single mutation, while co-occurrence of two, three, four or five mutations, within the same gene or in more than one, was found in seven (18%), four (11%), one (3%) and two patients (5%), respectively. Epigenetic modifiers (DNMT3A, TET2, ASXL1) were the most frequently mutated genes: 38 mutations with a median VAF of 6.5% detected in 32 patients. DNA repair genes (PPM1D, TP53, CHEK2, ATM) were the second most frequently mutated: 11 mutations at a median VAF of 4% were detected in 9 patients. 7 mutations in genes encoding for the cohesin complex (SMC3, SMC1A, RAD21, STAG2) were found in 6 patients, with a median VAF of 5%. A non-simultaneous cfDNA sequencing by FoundationOne Liquid CDx assay (324-gene panel) was performed in 9 patients for tumor profiling. In 2 out of 3 tested cases the presence of CH was confirmed in plasma liquid biopsy. 4 patients with no detectable CH by the targeted blood sequencing subsequently were found having CH mutations in plasma NGS, on average 45 months apart. To note, as many as 5 out of the 19 detected mutated genes (PPM1D, SMC3, SMC1A, PRPF8, ZRSR2) are not part of the FDA-approved NGS panel used for cfDNA profiling in solid tumors. Conclusion: We found a consistent prevalence of CH in patients with NSCLC by using a sequencing approach targeted for hematologic disorders. Prognostic implications of CH are under investigation and will be evaluated in the full cohort. Citation Format: Marco Tagliamento, Christophe Marzac, Mihaela Aldea, Damien Vasseur, Arnaud Bayle, Anas Gazzah, Maud Ngocamus, Claudio Nicotra, Julieta Rodriguez, Antonin Levy, Capucine Baldini, Santiago Ponce, Felix Blanc-Durand, Etienne Rouleau, Antoine Italiano, Ludovic Lacroix, Luc Friboulet, David Planchard, Fabrice Barlesi, Yohann Loriot, Jean-Baptiste Micol, Benjamin Besse. Molecular landscape of clonal hematopoiesis in patients with lung cancer: First results of the CHIC study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4526.
By means of an unbiased, automated fluorescence microscopy-based screen, we identified the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib as potent enhancers of the differentiation of HL-60 acute myeloid leukemia (AML) cells exposed to suboptimal concentrations of vitamin A (all-trans retinoic acid, ATRA) or vitamin D (1α,25-hydroxycholecalciferol, VD). Erlotinib and gefitinib alone did not promote differentiation, yet stimulated the acquisition of morphological and biochemical maturation markers (including the expression of CD11b and CD14 as well as increased NADPH oxidase activity) when combined with either ATRA or VD. Moreover, the combination of erlotinib and ATRA or VD synergistically induced all the processes that are normally linked to terminal hematopoietic differentiation, namely, a delayed proliferation arrest in the G0/G1 phase of the cell cycle, cellular senescence, and apoptosis. Erlotinib potently inhibited the (auto)phosphorylation of mitogen-activated protein kinase 14 (MAPK14, best known as p38MAPK) and SRC family kinases (SFKs). If combined with the administration of ATRA or VD, the inhibition of p38MAPK or SFKs with specific pharmacological agents mimicked the pro-differentiation activity of erlotinib. These data were obtained with 2 distinct AML cell lines (HL-60 and MOLM-13 cells) and could be confirmed on primary leukemic blasts isolated from the circulation of AML patients. Altogether, these findings point to a new regimen for the treatment of AML, in which naturally occurring pro-differentiation agents (ATRA or VD) may be combined with EGFR inhibitors.
