Affymetrix SNP array data for mammary tumors that recurred after inactivation of the oncogenic PIK3CA-H1047R. Mus musculus

Gain-of-function mutation of PIK3CA represents one of the most common oncogenic events in human malignancy, making PI3K an attractive target for cancer therapy. Despite the great promise of targeted therapy, drug resistance is likely to develop, causing treatment failure. To elucidate resistance mechanisms to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing PIK3CA-H1047R. Surprisingly, the majority of mammary tumors induced by PIK3CA-H1047R expression recurred following PIK3CA-H1047R inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including spontaneous focal amplification of c-Met or c-Myc. While amplification of c-Met allowed tumor survival dependent on activation of endogenous PI3K, tumors with amplification of c-Myc become independent of the PI3K pathway. Functional analyses further demonstrated that c-Myc contributed to tumors’ independence of oncogene and resistance to PI3K inhibition. Together, our data suggest that MYC elevation in tumors may be a potential mechanism conferring resistance to current PI3K-targeted therapies. Overall design: Affymetrix SNP array analysis was performed with Mouse Diversity Genotyping Arrays (Affymetrix) on genomic DNA extracted from frozen biopsies of 6 recurrent mouse mammary tumor samples. Copy number analysis was performed for the mouse mammary tumors using genomic DNA from normal mammary tissue as the reference for copy number inference.

PIK3CA的功能获得性突变（gain-of-function mutation）是人类恶性肿瘤中最常见的致癌事件之一，使得磷脂酰肌醇3-激酶（PI3K）成为癌症治疗的极具吸引力的靶点。尽管靶向疗法展现出巨大应用前景，但耐药性极易产生，进而导致治疗失败。为阐明PI3K靶向疗法的耐药机制，我们构建了条件性表达PIK3CA-H1047R的乳腺癌小鼠模型。令人意外的是，由PIK3CA-H1047R表达诱导的大多数乳腺肿瘤在PIK3CA-H1047R失活后出现复发。对复发肿瘤的基因组分析揭示了多种病变，包括c-Met或c-Myc的自发性局灶扩增。其中，c-Met扩增可使肿瘤依赖内源性PI3K的激活而存活，而携带c-Myc扩增的肿瘤则不再依赖PI3K信号通路。功能分析进一步证实，c-Myc可促使肿瘤脱离致癌基因依赖，并对PI3K抑制产生耐药性。综上，本研究数据表明，肿瘤中MYC的高表达可能是赋予当前PI3K靶向疗法耐药性的潜在机制。

总体实验设计：使用小鼠多样性基因分型阵列（Mouse Diversity Genotyping Arrays，Affymetrix）对6例复发小鼠乳腺肿瘤样本的冷冻活检组织提取的基因组DNA进行Affymetrix SNP芯片分析。以正常乳腺组织的基因组DNA作为拷贝数推断的参照，对小鼠乳腺肿瘤开展拷贝数分析。