BRCA1 is a susceptibility gene for breast and ovarian cancer with growth-inhibitory activity for which the mechanism of action remains unclear. When introduced into cells, BRCA1 inhibits growth of some but not all cell lines. In an attempt to uncover the mechanism of growth suppression by BRCA1, we examined a panel of cell lines for their ability to reduce colony outgrowth in response to BRCA1 overexpression. Of all variables tested, only those cells with wild-type pRb were sensitive to BRCA1-induced growth suppression. In cells with an intact rb gene, inactivation of pRb by HPV E7 abrogates the growth arrest imposed by BRCA1. In accordance with these observations, we found that BRCA1 could not suppress BrdUrd uptake in primary fibroblasts from rb؊/؊ mice and exhibited an intermediate ability to inhibit DNA synthesis in rb؉/؊ as compared with rb؉/؉ cells. We further found that the BRCA1 protein complexes with the hypophosphorylated form of pRb. This binding is localized to amino acids 304 -394 of BRCA1 protein and requires the ABC domain of pRb. In-frame deletion of BRCA1 fragment involved in interaction with pRb completely abolished the growth-suppressive property of BRCA1. Although it has been reported that BRCA1 interacts with p53, we find the p53 status did not affect the ability of BRCA1 to suppress colony formation. Our data suggest that the growth suppressor function of BRCA1 depends, at least in part, on Rb. G ermline mutations in BRCA1 are found in Ϸ50-60% of hereditary breast and ovarian cancers (1). Despite the unequivocal role of BRCA1 in familial breast cancer susceptibility, the biological function of the BRCA1 protein remains unclear. Experimental data suggest that BRCA1 may be a negative regulator of cell growth. Attenuation of BRCA1 synthesis by antisense oligonucleotide increased the proliferative rate of both benign and malignant mammary epithelial cells in culture (2), and BRCA1 expression decreased the capacity of MCF7 breast cancer cells to form tumors in nude mice (3). However, BRCA1 expression increases as cells progress through the G 1 and S phases of the cell cycle (4, 5). Furthermore, homozygous BRCA1 mutant mice died at day 7.5 of embryogenesis with evidence of abnormal cessation of cellular proliferation accompanied by high levels of the CDK inhibitor p21 and low levels of cyclin E and mdm2 (6, 7). Recently, colocalization and physical interaction of BRCA1 with Rad51 protein has raised the possibility that BRCA1 is involved in DNA repair (8). Moreover, the COOH terminus of the BRCA1 protein can activate transcription in in vitro experiments (9, 10) and coactivate transcription of p53-regulated genes (11,12).The experimental biology of BRCA1 therefore suggests that BRCA1 may have different functions, each best manifested in specific study systems and cell lines. Herein, we show that BRCA1 binds preferentially to the hypophosphorylated form of Rb and that the growth-suppressive phenotype of BRCA1 depends on the presence of a functional Rb protein. These data indicate the complexity of ...

BRCA1 gene is a tumor suppressor for breast and ovarian cancers with the putative role in DNA repair and transcription. To characterize the role of BRCA1 in transcriptional regulation, we analyzed gene expression profiles of mouse embryonic stem cells deficient in BRCA1 using microarray technology. We found that loss of BRCA1 correlated with decreased expression of several groups of genes including stress response genes, cytoskeleton genes, and genes involved in protein synthesis and degradation. Previous study showed that BRCA1 is a transcriptional co-activator of p53 protein; however the majority of p53 target genes remained at the same expression levels in BRCA1 knockout cells as in the wild type cells. The only p53 target gene downregulated with the loss of BRCA1 was 14-3-3, a major G 2 /M checkpoint control gene. Similar to cells with decreased 14-3-3 activity, BRCA1-deficient cells were unable to sustain G 2 /M growth arrest after exposure to ionizing radiation. We find that BRCA1 induction of 14-3-3 requires the presence of wild type p53 and can be regulated by a minimal p53 response element.

9610 Background: First-line immunotherapy with/without chemotherapy is standard of care for patients (pts) with advanced NSCLC; however, there is a need for effective treatment options after progression on a prior immune checkpoint inhibitor (ICI). Cabozantinib (C) may augment response to ICI by inhibiting kinases implicated in suppressing immune cell responses and has shown encouraging clinical activity in combination with ICI in other tumor types including RCC and HCC. COSMIC-021, a multicenter phase 1b study, is evaluating the combination of C with atezolizumab (A) in various solid tumors (NCT03170960). We report results from cohort 7 in NSCLC pts after prior ICI therapy. Methods: Eligible pts had ECOG performance status (PS) 0-1 and radiographic progression after one prior anti-PD-1/PD-L1 ICI given alone or in combination with chemotherapy for metastatic non-squamous NSCLC. Up to 2 lines of prior systemic anticancer therapies were permitted. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for the first year and Q12W thereafter. Primary endpoint is ORR per RECIST 1.1 by investigator. Other endpoints include safety, duration of response (DOR), progression-free survival, and overall survival. Results: Thirty pts with advanced NSCLC were enrolled. Median age was 67 yrs (range 41, 81), 43% were male, 57% had ECOG PS 1, and 23% had liver metastases. Median duration of prior ICI therapy was 4.8 months (mo; range 0.8, 29), and 15 (50%) pts were refractory to prior ICI (progressive disease as best response). As of December 20, 2019, the median follow-up was 8.9 mo (range 5, 20) with 9 (30%) pts continuing study treatment. The most common treatment related adverse events (TRAEs) of any grade were diarrhea (53%), fatigue (37%), nausea (23%), decreased appetite (20%), palmar-plantar erythrodysesthesia (20%) and vomiting (20%). Grade 3/4 TRAEs occurred in 14 (47%) pts, and 1 (3.3%) had grade 5 TRAEs of myocarditis and pneumonitis. Confirmed ORR per RECIST 1.1 was 23% (7 of 30 pts; all partial responses including 3 pts refractory to prior ICI). Time to response was 1.4 mo (range 1, 3), and median DOR was 5.6 mo (range 2.6, 6.9). DCR (CR+PR+SD) was 83%. Conclusions: The combination of C and A had an acceptable safety profile and showed encouraging clinical activity in pts with advanced NSCLC who had progressed after prior ICI therapy. The response rate was greater than previously observed with C monotherapy. Due to the promising data, enrollment in this cohort has been expanded and is ongoing. Clinical trial information: NCT03170960 .

Objective The aim of this study is to investigate the impact of missed chemotherapy administrations (MCA) on the prognosis of non–small cell lung cancer (NSCLC) patients treated with definitive chemoradiation therapy (CRT). Materials and Methods In total, 97 patients with NSCLC treated with definitive CRT were assessed for MCA due to toxicities. Logistic regression was used to determine factors associated with MCA. Kaplan-Meier curves, log-rank tests, and Cox Proportional Hazards models were conducted. Results MCA occurred in 39% (n = 38) of the patients. Median overall survival was 9.6 months for patients with MCA compared with 24.3 months for those receiving all doses (P = 0.004). MCA due to decline in performance status was associated with the worst survival (4.6 mo) followed by allergic reaction (10.0 mo), hematologic toxicity (11 mo), and esophagitis (17.2 mo, P = 0.027). In multivariate models, MCA was associated with higher mortality (hazard ratio, 1.97; P = 0.01) and worse progression-free survival (hazard ratio, 1.96; P = 0. 009). Conclusions MCA correlated with worse prognosis and increased mortality. Methods to reduce toxicity may improve administration of all chemotherapy doses and increase overall survival in NSCLC treated with CRT.