Transcriptomic Mapping of Non-Small Cell Lung Cancer K-RAS p.G12C Mutated Tumors: Identification of Surfaceome Targets and Immunologic Correlates

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.


q TIAM1
The protein encoded by this gene is a member of the CMGC family of serine/threonine protein kinases. This kinase is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression and G1/S transition. The activity of this kinase first appears in mid-G1 phase. which is controlled by the regulatory subunits including Dtype cyclins and members of INK4 family of CDK inhibitors. This kinase. as well as CDK4. has been shown to phosphorylate. and thus regulate the activity of. tumor suppressor protein Rb q CDK6 This gene encodes a sialoglycoprotein that is expressed on mature granulocytes and B cells and modulates growth and differentiation signals to these cells. The precursor protein is cleaved to a short 32 amino acid mature peptide which is anchored via a glycosyl phosphatidylinositol (GPI) link to the cell surface.

q CD24
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A. H2B. H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation. cell cycle progression and developmental events. Isoform 3 lacks active site residues and therefore is catalytically inactive. Represses MEF2-dependent transcription by recruiting HDAC1 and/or HDAC3.

Downregulated Genes q VTCN1
Negatively regulates T-cell-mediated immune response by inhibiting T-cell activation. proliferation. cytokine production and development of cytotoxicity. When expressed on the cell surface of tumor macrophages. plays an important role. together with regulatory T-cells (Treg). in the suppression of tumor-associated antigen-specific T-cell immunity. Involved in promoting epithelial cell transformation.
Encodes the insulin receptor substrate 2. a cytoplasmic signaling molecule that mediates effects of insulin. insulin-like growth factor 1. and other cytokines by acting as a molecular adaptor between diverse receptor tyrosine kinases and downstream effectors. The product of this gene is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation. as well as by an interleukin 4 receptor-associated kinase in response to IL4 treatment q IRS2

Upregulated Genes
Plays essential roles in both eye and limb development. Probable regulator of osteoblast differentiation.

q SMOC1
Atypical homeodomain protein which does not bind DNA and is required to modulate cardiac growth and development. Acts via its interaction with SRF. thereby modulating the expression of SRF-dependent cardiacspecific genes and cardiac development. Prevents SRF-dependent transcription either by inhibiting SRF binding to DNA or by recruiting histone deacetylase (HDAC) proteins that prevent transcription by SRF. May act as a tumor suppressor. Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and assists in chaperone-mediated protein refolding q HOPX This gene was initially identified as a homolog of the feline sarcoma viral oncogene v-kit and is often referred to as proto-oncogene c-Kit. The canonical form of this glycosylated transmembrane protein has an Nterminal extracellular region with five immunoglobulin-like domains. a transmembrane region. and an intracellular tyrosine kinase domain at the C-terminus. Upon activation by its cytokine ligand. stem cell factor (SCF). this protein phosphorylates multiple intracellular proteins that play a role in the proliferation. differentiation. migration and apoptosis of many cell types and thereby plays an important role in hematopoiesis. stem cell maintenance. gametogenesis. melanogenesis. and in mast cell development. migration and function.

q KIT
The encoded protein has 3'.5'-cyclic-AMP phosphodiesterase activity and degrades cAMP. which acts as a signal transduction molecule in multiple cell types.

q PDE4D
In complex with CLCF1. forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development (Probable). May also play a regulatory role in the immune system.

q CRLF1
Supplementary