Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms.
Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms.
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PIK 3CA功能获得性突变是人类恶性肿瘤中常见的致癌事件，使得PI 3 K成为癌症治疗的有吸引力的靶标。尽管靶向治疗有很大的希望，但耐药性往往会发展，导致治疗失败。为了阐明对PI 3 K靶向治疗的抗性机制，我们构建了条件性表达人PIK 3CAH 1047 R的乳腺癌小鼠模型。令人惊讶的是，大多数PIK 3CAH 1047 R驱动的乳腺肿瘤在PIK 3CAH 1047 R失活后复发。复发肿瘤的基因组分析显示多处病变，包括c-Met或c-Myc的局灶性扩增。虽然c-Met扩增允许依赖于内源性PI 3 K激活的肿瘤存活，但具有c-Myc扩增的肿瘤变得不依赖于PI 3 K途径。功能分析表明，c-Myc有助于癌基因的独立性和抵抗PI 3 K抑制。重要的是，PI 3 KCA突变和c-MYC水平增加共同发生在相当一部分人乳腺肿瘤中。总之，这些数据表明，c-MYC升高代表了肿瘤对当前PI 3 K靶向治疗产生耐药性的潜在机制。
PIK3CA gain-of-function mutations are a common oncogenic event in human malignancy, making PI3K an attractive target for cancer therapy. Despite the great promise of targeted therapy, resistance often develops, resulting in treatment failure. To elucidate mechanisms of resistance to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing human PIK3CAH1047R. Surprisingly, most PIK3CAH1047R-driven mammary tumors recurred following PIK3CAH1047R inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including focal amplification of c-Met or c-Myc. While c-Met amplification allowed tumor survival dependent on activation of endogenous PI3K, tumors with c-Myc amplification became independent of the PI3K pathway. Functional analyses demonstrated that c-Myc contributed to oncogene independence and resistance to PI3K inhibition. Importantly, PI3KCA mutations and increased c-MYC levels co-occur in a substantial fraction of human breast tumors. Together, these data suggest that c-MYC elevation represents a potential mechanism by which tumors develop resistance to current PI3K-targeted therapies.
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有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
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影响因子：
4.8
作者：
Gunther, EJ;Belka, GK;Chodosh, LA
通讯作者：
Chodosh, LA
影响因子：
50.3
作者：
Moody, SE;Perez, D;Chodosh, LA
通讯作者：
Chodosh, LA
影响因子：
11.2
作者：
Stemke-Hale K;Gonzalez-Angulo AM;Lluch A;Neve RM;Kuo WL;Davies M;Carey M;Hu Z;Guan Y;Sahin A;Symmans WF;Pusztai L;Nolden LK;Horlings H;Berns K;Hung MC;van de Vijver MJ;Valero V;Gray JW;Bernards R;Mills GB;Hennessy BT
通讯作者：
Hennessy BT
影响因子：
5.7
作者：
Tibes, Raoul;Qiu, YiHua;Kornblau, Steven M.
通讯作者：
Kornblau, Steven M.