WCLC 2022 | Molecular drivers and therapeutic targets for neuroendocrine transformation in lung cancer

I spoke about molecular drivers and therapeutic targets of lung cancer transformation. So to speak, I spoke exclusively about EGFR-mutant lung adenocarcinoma that transformed to small cell lung cancer as a mechanism of resistance to tyrosine kinase inhibitors. This phenomena has been noted for almost a decade ago. This was first reported in 2011 and since then it had been reported by various groups. In our study, we, for the first time, did a multi-omic analysis on what we called a combined histology tumor, that we had 11 cases where the lung adenocarcinoma component and the small cell component were in the same spatial region.

We performed microdissection of these samples and we analyzed them with various platforms like whole exome sequencing, bulk RNA-sequencing, methylation analysis, and immunohistochemistry. The results really gave us a lot of insight into these very understudied tumors. We have known about this phenomena, but it hasn’t been studied so far. So what our genomic analysis or the analysis with whole exome sequencing tool does, is that, P53 and RB1 loss was one of the most characteristic feature of these tumors, so almost all of them had a loss-of-function mutation in P53 and RB1, or RB1 was functionally lost in these tumors, and so that seems to be one of the main genomic characteristics.

What we learned from RNA seq analysis is that several pathways gets either turned on and turned off during this process of transformation. Some of the important targets, that I would like to point out, is that we observed Notch inhibition and we also saw up regulation of several PRC2 Complex genes. We saw up regulation of DNA damage response genes, as a sort of a predictive pathways that could predict these tumors that are more poised to transform. We also saw a suppression in the anti-tumor gene.

So we found several immune pathways to be suppressed, in these tumors that were transforming to small cell lung cancer, so I think in terms of the pathways that we find the most interesting, and that we are going to follow up in future studies, would be the AKT signaling pathway, the Wnt signaling pathway, and several epigenetic modulators. I think one of the more characteristic features is the suppression of the anti-tumor immune response, which we are definitely going to follow up in further studies.

In terms of therapeutic targets, we found AKT inhibition to be effective in an EGFR mutant mouse model, where we found that, when you combine AKT inhibition with osimertinib, which is a standard therapy for these EGFR-mutant lung adenocarcinoma, the combination actually performed better in-vivo studies, or in our mouse models, than either of the single agents alone.

That is one of the therapeutic targets that we have identified. I’m sure there are many, it’s an active area of investigation, and I would be very interested to see what comes up in future studies, but I think this study is important because this not only tells us, gives us an insight into the biology of these tumors, but it also points out to several pathways and targets that could be followed on, in future studies, and also additional targets that I think needs investigation further.