Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation

Abstract

Background Lineage plasticity, the ability to transdifferentiate among distinct phenotypic identities, facilitates therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transformation in the context of acquired resistance to targeted inhibition of driver mutations. LUAD-to-LUSC transdifferentiation, occurring in up to 9% of EGFR-mutant patients relapsed on osimertinib, is associated with notably poor prognosis. We hypothesized that multi-parameter profiling of the components of mixed histology (LUAD/LUSC) tumors could provide insight into factors licensing lineage plasticity between these histologies. Methods We performed genomic, epigenomics, transcriptomics and protein analyses of microdissected LUAD and LUSC components from mixed histology tumors, pre-/post-transformation tumors and reference non-transformed LUAD and LUSC samples. We validated our findings through genetic manipulation of preclinical models in vitro and in vivo and performed patient-derived xenograft (PDX) treatments to validate potential therapeutic targets in a LUAD PDX model acquiring LUSC features after osimertinib treatment. Results Our data suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events. We observed consistent relative upregulation of PI3K/AKT, MYC and PRC2 pathway genes. Concurrent activation of PI3K/AKT and MYC induced squamous features in EGFR-mutant LUAD preclinical models. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse with squamous-features in an EGFR-mutant patient-derived xenograft model, and inhibition of EZH1/2 or PI3K/AKT signaling re-sensitized resistant squamous-like tumors to osimertinib. Conclusions Our findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and potential therapeutic targets to constrain or prevent lineage plasticity.

Non‐small cell lung carcinomas with diffuse coexpression of TTF1 and p40: clinicopathological and genomic features of 14 rare biphenotypic tumours

“…AKT and MYC have been previously implicated as drivers of lineage plasticity, 22 and these factors were specifically identified as mediators of squamous transdifferentiation of LUADs. 23 Amplification of these genes could thus contribute to the induction of the dual phenotype in this cohort of tumours.…”

Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation

“…It’s worth noting that a recent study on squamous transitioned lung cancer indicates a potential role of Wnt signaling in promoting AST, 20 e.g., Wnt pathway is upregulated in transitioned lung cancer after Osimertinib resistance. Since this study mainly compares the Wnt pathway between two time points, before and after TKI resistance, it might not be able to uncover the dynamic changes of Wnt signaling.…”

“…LKB1 (also named as serine-threonine kinase 11, STK11) is mutated in ~17% human lung ADC 20 whereas its mutation rate is enriched in lung AdSCC, averaging at 39.66% (ranging from 22 to 66% in multiple studies). 12,[20][21][22][23] A recent study has analyzed LKB1 mutations in relapsed patients with potential adeno-to-squamous transdifferentiation, which shows a relatively low rate at 14.3% (1 out of 7).…”

Scutellaria barbata D.Don (SBD) extracts suppressed tumor growth, metastasis and angiogenesis in Prostate cancer via PI3K/Akt pathway

“…A large amount of evidence indicates that PI3K/Akt signalling pathway is an important regulator involved in cell proliferation and metastasis [ 31 , 32 ]. Interestingly, we observed the inactivation of PI3K/AKT signalling pathway in PCa cell treated by SBD.…”