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Somatic Loss of Wild-Type Kras Enhances Cancer Fitness and Promotes MEK Dependence

ABSTRACT: Investigating therapeutic “outliers” that show exceptional responses to anti-cancer treatment can reveal unexpected synthetic lethal interactions and uncover biomarkers of drug sensitivity. Preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D “knock-in” mice showed that the MEK inhibitor PD0325901 (PD901) extended survival while the pan-phosphoinositide 3-kinase (PI3K) inhibitor GDC-0941 was ineffective. One outlier PD901-treated AML had a four-fold improvement in survival, and exhibited intrinsic drug resistance at relapse. This resistant leukemia arose from an evolutionary precursor of the dominant drug-sensitive AML, and KrasG12D was duplicated in both AML clones. Loss of wild-type (WT) Kras both enhanced the competitive fitness of the dominant clone and rendered it more sensitive to MEK inhibition. Similarly, colorectal cancer cell lines with loss of WT KRAS are more sensitive to MEK inhibitors, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized a heterozygous mutant HCT116 cells to drug treatment. In a large prospectively characterized cohort of tumors from patients with advanced and metastatic cancers, 642 of 1168 (55%) with KRAS mutations exhibited allelic imbalance. Together, these studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer, and can modulate competitive fitness and MEK dependency.

ORGANISM(S): Mus musculus

PROVIDER: GSE92682 | GEO | 2016/12/22

SECONDARY ACCESSION(S): PRJNA358327

REPOSITORIES: GEO

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Project description:Somatic NOTCH1 mutations are found in ~60% of T lineage acute lymphoblastic leukemias (T-ALLs). Notch1 is cleaved by γ secretase to generate activated Notch intracellular domain (NICD) proteins. The NOTCH1 mutations found in T-ALL constitutively activate Notch1 signaling by increasing NICD levels. Genetic alterations in components of the Ras/PI3 kinase (PI3K)/Akt pathway are also highly prevalent in T-ALL, and often coexist with NOTCH1 mutations. Exposing a T-ALL cell line to the PI3 kinase (PI3K) inhibitor GDC-0941 generated drug resistant clones that down-regulated NICD expression. To address the in vivo relevance of this unexpected observation, we transplanted primary wild-type (WT) and KrasG12D mutant T-ALLs into recipient mice, and treated them with GDC-0941 alone and in combination with the MEK inhibitor PD0325901 (PD901). Although many leukemias responded dramatically to these targeted agents in vivo, drug-resistant clones invariably emerged. Multiple resistant T-ALLs lost NICD expression through mechanisms that included loss of Notch1 mutations found in the parental T-ALL. These GDC-0941-resistant leukemias exhibited reduced expression of many Notch1 target genes, elevated levels of phosphorylated Akt (pAkt), and displayed cross-resistance to γ secretase inhibitors (GSIs). Consistent with these data, inhibiting Notch1 activity in T-ALL cells enhanced PI3K signaling, providing a likely mechanism for in vivo selection against clones with Notch1 pathway activation. Thus, oncogenic Notch1 mutations that promote clonal outgrowth during malignant transformation unexpectedly “switch” to become deleterious during treatment with a PI3K inhibitor. These data advance our understanding of T-ALL pathogenesis and have implications for implementing new therapeutic regimens. We analyzed 28 mouse T-ALL samples obtained after in vivo treatment with GDC-0941 alone or GDC-0941 + PD0325901. These T-ALL samples are either Kras wild type or harbor a KrasG12D mutations.

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Somatic Loss of Wild-Type Kras Enhances Cancer Fitness and Promotes MEK Dependence

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