Abstract
Targeting K-RAS-mutant non-small cell lung cancer (NSCLC) with novel inhibitors has shown promising results with the recent approval of sotorasib in this indication. However, progression to this agent is expected, as it has previously been observed with other inhibitors. Recently, new immune therapeutics, including vectorized compounds with antibodies or modulators of the host immune response, have demonstrated clinical activity. By interrogating massive datasets, including TCGA, we identified genes that code for surface membrane proteins that are selectively expressed in K-RAS mutated NSCLC and that could be used to vectorize novel therapies. Two genes, CLDN10 and TMPRSS6, were selected for their clear differentiation. In addition, we discovered immunologic correlates of outcome that were clearly de-regulated in this particular tumor type and we matched them with immune cell populations. In conclusion, our article describes membrane proteins and immunologic correlates that could be used to better select and optimize current therapies.
Highlights
Identification of the key molecular alterations that drive oncogenesis is one of the main objectives in current cancer research [1]
In the present article we identify novel genes upregulated in KRAS G12C mutated non-small cell lung cancer (NSCLC) that could be used as targets to vectorize compounds against these tumors, or as surrogates of immune activation, to select patients or explore combinations with novel immune therapies
We selected a set of genes that were modified in tumors with KRAS G12C mutations, including the upregulated HOPX, PDED4 and CRLF1 genes, that were in addition linked with favorable prognosis in terms of first progression (FP) and overall survival (OS)
Summary
Identification of the key molecular alterations that drive oncogenesis is one of the main objectives in current cancer research [1]. In the last few decades much effort has been put on the development of anticancer treatments selectively targeting gene products that become dysregulated as a consequence of those oncogenic alterations This strategy, combined with the generalization of the use of molecular diagnosis, has led to the application of more individualized and selective treatments which has conducted to a very significantly improvement in patient survival in several types of cancer [2, 3]. The presence of a thiol group at Cys 12 of K-RAS G12C offered an opportunity to develop inhibitors against this specific mutant, which is present with a notable frequency in certain cancer types and in NSCLC [6] Following this strategy, a new family of compounds aimed at targeting K-RAS G12C has been developed. Other compounds acting on the same target are currently in clinical development [9]
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