See article, p. 342

  • The BCL2 Gly101Val mutation was identified in patients with CLL at progression on venetoclax.

  • The mutation impairs BCL2 binding to venetoclax and is sufficient to induce acquired resistance.

  • Detection of the Gly101Val mutation may be an early biomarker of clinical relapse.


The selective BCL2 inhibitor venetoclax induces rapid clinical responses in patients with previously treated chronic lymphocytic leukemia (CLL), but its long-term efficacy can be limited by acquisition of resistance and disease relapse. To identify mechanisms of secondary venetoclax resistance in CLL, Blomberyand colleagues sequenced matched pretreatment and postprogression samples from patients with relapsed CLL who were treated with venetoclax. In 7 of 15 patients with CLL-type progression on venetoclax, a recurrent point mutation in BCL2 was detected exclusively in post-venetoclax but not pretreatment samples. This mutation resulted in substitution of valine at glycine 101 (Gly101Val) in BCL2 and was identified at various subclonal frequencies prior to the emergence of clinical disease progression. Expression of this BCL2 mutation was sufficient to confer acquired resistance to venetoclax in vitro; the Gly101Val mutation diminished binding of venetoclax to BCL2, thereby impairing the ability of venetoclax to displace proapoptotic proteins from mutant BCL2, and provided a selective growth advantage over wild-type cells when continuously exposed to venetoclax. Further analysis of cells isolated from a patient at progression identified a second subclone lacking the Gly101Val mutation but harboring increased BCL-XL expression, indicating that multiple routes to resistance may be operating independently in an individual patient, collectively contributing to leukemia relapse. These findings define a recurring mechanism of acquired resistance to venetoclax in patients with CLL and suggest that the Gly101Val mutation may represent an early biomarker of future clinical disease progression.

See article, p. 354

  • Venetoclax with tamoxifen was assessed in ER+ and BCL2+ metastatic breast cancer in a phase Ib study.

  • The combination was well tolerated and elicited encouraging antitumor activity.

  • Metabolic responses detected by FDG-PET may be an early marker of treatment responses.


The antiapoptotic protein BCL2 is overexpressed in many primary estrogen receptor–positive (ER+) breast cancers, and preclinical studies have shown that the BCL2 inhibitor venetoclax synergizes with the selective ER modulator tamoxifen to enhance tumor cell apoptosis in patient-derived xenograft models of ER+ breast cancer. These findings prompted Lok, Whittle, and colleagues to assess the safety and preliminary efficacy of daily treatment with tamoxifen and venetoclax in a phase Ib dose-escalation and expansion study in patients with ER+ and BCL2+ metastatic breast cancer. The combination was well tolerated, with the most common adverse events being cytopenia and nausea, and no dose-limiting toxicities were observed. In the dose-escalation component of the study, the maximum tolerated dose was not reached and 800 mg was selected as the recommended phase II dose (RP2D). Among 24 patients treated at this RP2D, the objective response rate was 54%, including one complete response and 12 partial responses, and the clinical benefit rate was 75%; of note, tumor responses or prolonged stable disease was observed in 8 of 12 patients who had been heavily pretreated. In addition, objective clinical responses correlated with partial metabolic response as measured by FDG-PET after four weeks of therapy and with decreased levels of ESR1 circulating tumor DNA. These results demonstrate that venetoclax plus tamoxifen is safe and has promising antitumor activity in patients with ER+ and BCL2+ metastatic breast cancer, and support further clinical trials that combine venetoclax and endocrine therapy in this solid tumor.

See article, p. 370

  • In a phase II trial, combined azacitidine and nivolumab achieved responses in patients with AML.

  • Nivolumab is well tolerated in patients with AML in combination with azacitidine.

  • Hypomethylating agents may enhance the clinical efficacy of immune checkpoint inhibitors.


Hypomethylating agents (HMA),such as azacitidine, are the standard of care for older patients with acute myeloid leukemia (AML) who are not eligible for induction therapy; however, these agents also induce the upregulation of immunosuppressive genes such as the immune checkpoints PD-1 and PD-L1. Because single-agent PD-1/PD-L1 inhibitors have not been efficacious in patients with AML, Daver and colleagues evaluated the safety and efficacy of azacytidine in combination with the anti–PD-L1 antibody nivolumab in a phase II trial in 70 patients with relapsed AML. The cohort exhibited a median overall survival (OS) of 11 months, compared to historical OSs of 4 to 6 months for patients with AML treated with HMA-based therapies, and the overall response rate was 33%, including 15 patients who exhibited complete remission. In particular, higher responses were observed in patients who harbored lower leukemic burden, a mutation in ASXL1, or elevated levels of CD3+ and CD8+ T cells in pretreatment bone marrow aspirate (BMA); moreover, the presence of >13.2% of pretherapy CD3+ T cells in BMA was highly predictive of response and thus a potential biomarker to stratify patients for combined HMA and anti–PD-1/PD-L1 therapy. Immune-mediated Grade 2 and Grade 3–4 toxicities each occurred in 11% of patients, but were manageable with early recognition and rapid intervention with steroids. Taken together, these findings indicate that hypomethylating agents in combination with anti–PD-L1/PD-L1 therapy is well tolerated, induces lymphocytic activation, and exhibits antitumor activity in patients with AML.

See article, p. 384

  • The multikinase RET inhibitor RXDX-105 achieved responses in RET inhibitor–naïve patients.

  • RXDX-105 is well tolerated and induces fewer side effects from VEGFR inhibition compared to older drugs.

  • RXDX-105 exhibited the greatest antitumor efficacy in patients with RET fusion–positive NSCLC.


Oncogenic activation of the receptor tyrosine kinase RET occurs by mutation (e.g., in thyroidcancer) and rearrangement (e.g., in lung cancer). RET-targeting multikinase inhibitors have exhibited modest clinical efficacy which is in part due to off-target toxicities associated with the more potent inhibition of other kinases such as VEGFR. Recently, the multikinase RET inhibitor RXDX-105 was shown to exhibit on-target antitumor efficacy while sparing VEGFR1/2 in preclinical animal models. In a phase I/Ib trial, Drilon and colleagues evaluated the safety, efficacy, and pharmacodynamics of RXDX-105 in 55 patients with solid tumors in the phase I dose-escalation portion of the study and 97 patients with RET- or RAF-driven solid tumors in the Ib dose-expansion portion of the study; of the 152 patients total, 82 harbored non–small cell lung cancer (NSCLC). RXDX-105 was found to be well tolerated and exhibited effective RET targeting. Of the eight patient cohorts in the Ib dose-expansion portion of the study, an overall response rate (ORR) of 19% was seen in patients with RET inhibitor–naïve RET fusion–positive lung cancers. Further, in this cohort, patients with tumors harboring a non-KIF5B–RET fusion exhibited an ORR of 67%, whereas no objective responses were observed in patients with KIF5B–RET tumors. These findings show that RXDX-105 is efficacious against RET-driven lung tumors and provide insight into multikinase drug design strategies.

See article, p. 396

  • BRAF and MEK inhibition promotes ER translocation of the MAPK pathway mediated by GRP78, KSR2, and SEC61.

  • ER translocation of the MAPK pathway is necessary for reactivation of ERK in the cytosol by PERK.

  • Activated ERK localizes to the nucleus and induces cytoprotective autophagy by phosphorylating ATF4.


The combination of BRAF and MEK inhibitors (BRAFi and MEKi) is currently the standard of care for BRAF-mutant melanoma with initial good responses, but patients eventually become resistant to combination therapy and progress. Several acquired resistance mechanisms have been described including ERK reactivation or endoplasmic reticulum (ER) stress response–associated autophagy. Ojha and colleagues report that ERK reactivation and autophagy are part of a unified mechanism of resistance to BRAF and MEK inhibition. They observed that treatment of a panel of BRAFi/MEKi-resistant and -sensitive melanoma cell lines and PDX models with BRAFi and MEKi promotes translocation of the entire MAPK pathway to the ER. ER translocation was mediated through binding of all MAPK proteins to the cytosolic scaffolding protein KSR2 that interacts with the ER chaperone GRP78. The GRP78–KSR2–MAPK complex is recruited to RAB5+ early endosomes and transported to the ER by the SEC61 translocase. Following translocation of the complex, ERK2 exits the ER back to the cytosol and is phosphorylated by the cytoplasmic domain of PERK, leading to its activation and nuclear transport. Nuclear phospho-ERK then induces cytoprotective autophagy by phosphorylation and stabilization of the ER stress response protein ATF4, which transcriptionally regulates autophagy. This drug resistance pathway was activated in BRAF- or BRAF/NRAS-mutant but not BRAF–wild-type tumor cells, suggesting that targeting components of this pathway such as GRP78 or using ERK inhibitors in combination with BRAFi and MEKi might be effective to overcome resistance in patients with melanoma.

See article, p. 416

  • The mevalonate pathway utilizes acetyl-CoA produced by ACLY to support KRAS-driven acinar-to-ductal metaplasia.

  • ACLY deficiency impairs pancreatitis-induced PanIN formation.

  • Treatment with BET inhibitors and statins suppresses PDAC cell proliferation and tumor growth.


Activating mutations in KRAS are common in pancreatic ductal adenocarcinoma (PDAC) and promote elevated histone acetylation in pancreatic acinar cells even prior to the appearance of tumors. Carrer and colleagues determined that the enzyme ATP-citrate lyase (ACLY) increases production ofacetyl-CoA in Kras-mutant pancreatic cells, which in turn drives acinar-ductal metaplasia (ADM) and tumorigenesis through acetyl-coA utilization for histone acetylation and the mevalonate pathway. In vitro, duct formation of collagen-embedded acinar cells was suppressed by targeting acetyl-CoA–dependent processes via treatment with JQ1, which targets BET family proteins that recognize acetylated histones, or atorvastatin, which targets the mevalonate pathway; for the latter treatment, supplementation with mevalonate-5-phosphate or cholesterol rescued duct formation. Deletion of Acly in a mouse model of pancreatic tumorigenesis reduced acetyl-CoA availability and histone acetylation and strongly impaired ADM. Acly deficiency also reduced tumor burden and extended overall survival in vivo. In PDAC cells, growth factor–induced AKT signaling promoted ACLY phosphorylation, leading to increased histone H3K27 acetylation at stroma-regulated gene promoters and enhancers. In a subcutaneous allograft tumor model, combined treatment with JQ1 and atorvastatin suppressed growth of KRAS-mutant PDAC. Collectively, these findings uncover coordinated metabolic and signaling roles of acetyl-coA in PDAC and provide a potential therapeutic strategy to target this disease.

See article, p. 436

  • PHF6 loss-of-function mutations are early events in human T-cell acute lymphoblastic leukemia.

  • Phf6 knockout disrupts HSC homeostasis and promotes long-term HSC self-renewal and reconstitution.

  • Phf6 loss accelerates oncogenic transformation and enhances leukemia-initiating cell activity.


Inactivating mutations and deletions in plant homeodomain factor 6 (PHF6) occur in approximately 20% of T-cell acute lymphoblastic leukemias (T-ALL), but their role in leukemogenesis is unclear. Following an analysis of whole-exome sequencing data that suggested that PHF6 mutations are early events in human T-ALL development, Wendorff and colleagues generated conditional Phf6 knockout mice to evaluate the role of PHF6 in hematopoietic stem cell (HSC) function and leukemia initiation. Inactivation of Phf6 in HSCs promoted their expansion, long-term self-renewal, and hematopoietic reconstitution capacity in association with increased chromatin accessibility loci at promoters of genes involved in HSC homeostasis. Phf6 loss also enhanced reconstitution capacity and protective quiescence in HSCs in response to chemotherapy-induced stress, further suggesting that disruption of HSC homeostasis caused by inactivation of PHF6 can support leukemic progression. Indeed, Phf6 loss accelerated transformation of NOTCH1-expressing bone marrow progenitor cells and significantly increased leukemia penetrance and mortality in mice. Moreover, Phf6-knockout tumors exhibited significantly increased leukemia-initiating cell activity in limiting dilution transplantation assays, supporting a role of Phf6 loss in promoting leukemic cell self-renewal. Consistent with these findings, gene expression programs associated with leukemic stem cell activity were enriched in both Phf6-knockout NOTCH1-induced T-ALL cells as well as human PHF6-mutant leukemia compared with wild-type controls. These findings suggest that inactivating PHF6 mutations are early drivers of T-ALL that promote HSC expansion and self-renewal capacity, create a permissive environment for oncogenic transformation, and enhance leukemia-initiating cell activity.

Note:In This Issue is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details.