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Supplementary Figures 1-6 from Interaction between MYC and MCL1 in the Genesis and Outcome of Non–Small-Cell Lung Cancer

Supplementary Table 2 from Interaction between MYC and MCL1 in the Genesis and Outcome of Non–Small-Cell Lung Cancer

MYC exerts both positive and negative functions in cancer cells, such that its procancerous effects are unmasked only after its anticancer effects are blocked. Here we used multiple mouse models of lung adenocarcinoma to identify genetic events that can cooperate with MYC activation to promote the genesis of non–small-cell lung cancer (NSCLC), the most common form of lung cancer in humans. MYC overexpression targeted to pulmonary alveolar cells was sufficient to induce lung adenomas and carcinomas. Tumorigenesis was assisted by either spontaneous mutations in Kras or experimental introduction of activated RAS, but investigations revealed that additional events were required to circumvent apoptosis, one of the most significant negative functions exerted by MYC. We determined that overexpression of the antiapoptotic protein MCL1 was sufficient to circumvent apoptosis in this setting. Previous clinical studies have indicated that prognosis of human NSCLC is not associated with MCL1, despite its overexpression in many NSCLCs. In reexamining the prognostic value in this setting, we found that MCL1 overexpression does correlate with poor patient survival, but only when accompanied by MYC overexpression. Our findings therefore produce a convergence of mouse and human results that explain how MCL1 can block an important negative consequence of MYC overexpression in both experimental models and clinical cases of NSCLC. Cancer Res; 71(6); 2212–21. ©2011 AACR.

Supplementary Figure Legends 1-6 from Interaction between MYC and MCL1 in the Genesis and Outcome of Non–Small-Cell Lung Cancer

Supplementary Table 1 from Interaction between MYC and MCL1 in the Genesis and Outcome of Non–Small-Cell Lung Cancer

Supplementary Methods from Interaction between MYC and MCL1 in the Genesis and Outcome of Non–Small-Cell Lung Cancer

MYC exerts both positive and negative functions in cancer cells, such that its procancerous effects are unmasked only after its anticancer effects are blocked. Here we used multiple mouse models of lung adenocarcinoma to identify genetic events that can cooperate with MYC activation to promote the genesis of non–small-cell lung cancer (NSCLC), the most common form of lung cancer in humans. MYC overexpression targeted to pulmonary alveolar cells was sufficient to induce lung adenomas and carcinomas. Tumorigenesis was assisted by either spontaneous mutations in Kras or experimental introduction of activated RAS, but investigations revealed that additional events were required to circumvent apoptosis, one of the most significant negative functions exerted by MYC. We determined that overexpression of the antiapoptotic protein MCL1 was sufficient to circumvent apoptosis in this setting. Previous clinical studies have indicated that prognosis of human NSCLC is not associated with MCL1, despite its overexpression in many NSCLCs. In reexamining the prognostic value in this setting, we found that MCL1 overexpression does correlate with poor patient survival, but only when accompanied by MYC overexpression. Our findings therefore produce a convergence of mouse and human results that explain how MCL1 can block an important negative consequence of MYC overexpression in both experimental models and clinical cases of NSCLC. Cancer Res; 71(6); 2212–21. ©2011 AACR.

Xenografts established directly from patient tumors mirror closely the histology of the primary tumors. Therefore, primary tumor xenografts (PTXG) may serve as important preclinical models to evaluate novel anti-cancer drugs. We previously reported that the ability of resected tumors to engraft in NOD-scid mice is a strong predictor of relapse after surgery and poorer prognosis in NSCLC patients, and thus may represent biologically more aggressive cancers (Clin Cancer Res 2011;17:134-41). Genomic characterization of PTXG would help identify genetic aberrations that drive malignant oncogenic pathways in NSCLC. We characterized the somatic copy number alterations (CNA) of 36 PTGX, consisting of 15 adenocarcinoma (ADC), 18 squamous cell carcinoma (SCC), 2 large cell neuroendocrine carcinoma (LCNEC) and 1 large cell carcinoma (LC), along with 34 patient normal samples as controls using Illumina Omni-1 Quad SNP arrays. The gene expression profiles of the 36 PTGX were analyzed using Illumina Omni-1 Quad HT-12 v4 arrays. Histology-specific recurrent regions of CNA observed in PTGX are concordant with the published and publicly available primary NSCLC CNAs. We identified 1053 genes with somatic copy number gains and 932 genes with somatic copy number losses that distinguish between SCC and ADC. From integrative analysis of mRNA expression and somatic CNAs, we identified 325 genes specific to ADC and 2232 specific to SCC that are well correlated. Gene candidates that are deregulated in ADC include WRN, STK35, SIX1; and genes that are over-expressed in SCC include SOX2, RNF13, WNK1, PIK3CA, TFRC, TP63, PAK2 suggesting there is differential deregulation of signaling pathways between these two subtypes of lung cancer. We have identified candidate gene signatures that distinguish between ADC and SCC from PTXG, suggesting these xenograft models can provide a valuable resource to study cancer biology and preclinical drug target evaluation in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5069. doi:1538-7445.AM2012-5069