Highlights from Recent Cancer Literature

Although BRCA1/2 alterations have been reported to predict platinum sensitivity, BRCA1 alterations have not consistently correlated with platinum sensitivity in clinical trials. Menghi and colleagues have now identified an explanation for these discordant results. They found that in contrast to BRCA1/2 mutations, BRCA1 promoter methylation (BRCA1meth) was not correlated with response to platinum agents in triple-negative breast and ovarian cancer patients. In vivo studies revealed that BRCA1meth is lost during chemotherapy treatment, leading to BRCA1 reactivation and acquired platinum resistance.

Expert Commentary: This study suggests that the reversibility of BRCA1meth may explain the inconsistent platinum efficacy observed in BRCA1-deficient tumors.

Menghi F, Banda K, Kumar P, Straub R, Dobrolecki L, Rodriguez IV, et al. Genomic and epigenomic BRCA alterations predict adaptive resistance and response to platinum-based therapy in patients with triple-negative breast and ovarian carcinomas. Science Translational Medicine 2022;14:eabn1926. doi: 10.1126/scitranslmed.abn1926.

Promoter methylation of the DNA damage response gene O⁶-methylguanine methyltransferase (MGMT) is a hallmark of glioma, conferring initial response to temozolomide. Invariably, resistance develops due to loss of mismatch repair (MMR) proteins. Lin and colleagues synthesized two compounds (KL-50 and KL-85) to deliver 2-fluoroethyl lesion at the O⁶-guanine, which rapidly modifies DNA into a secondary interstrand crosslink (ICL). In isogenic glioma models, MMR- and MGMT-deficient tumors were resistant to temozolomide but not to KL-50 or KL-85 through slow generation of DNA ICL's independent of MGMT. Moreover, KL-50 promoted activation of the DNA damage response and G₂ cell-cycle arrest in the absence of MMR. In vivo studies revealed marked efficacy compared with temozolomide in MGMT- and MMR-deficient models, with a favorable toxicity profile even at the highest doses.

Expert Commentary: This unique strategy of designing a temozolomide derivative that exploits MGMT loss offers new hope to drug-resistant glioma, using an established chemotherapy scaffold. Moreover, this approach opens the possibility of overcoming resistance to other chemotherapeutics such as anthracyclines and topoisomerase inhibitors.

Lin K, Gueble SE, Sundaram RK, Huseman ED, Bindra RS, Herzon SB. Mechanism-based design of agents that selectively target drug-resistant glioma. Science 2022;377:502–11.

Therapies blocking PRC2 activity are FDA approved and are implicated in promoting the effects of immunotherapy. Some cancers, however, exhibit loss of components of PRC2. Yan and colleagues reported that PRC2 disruption makes cancer, particularly malignant peripheral nerve sheath tumors (MPNST), less susceptible to immune attack. Loss of core components of PRC2, SUZ12, or EED was associated with an immune-desert phenotype and reduced interferon signatures in human and murine MPNSTs. These tumors grew faster and were resistant to checkpoint blockade immunotherapy (CBI). Resistance to CBI was reversed by intratumoral injection of a heat-inactivated–modified vaccinia virus Ankara, which restored the IFN response in tumors. Mechanistically, the authors showed that loss of repressive H3K27me3 marks by PRC2 caused diffusion of the transcriptional-enhancing H3K27 acetyl marks, reducing gene expression of IFN-related genes.

Expert Commentary: The activity of PRC2 in controlling cancer immunity varies across tumor types. MPNSTs are selected to lose PRC2 function to dampen IFN-driven immune responses.

Yan J, Chen Y, Patel AJ, Warda S, Lee CJ, Nixon BG, et al. Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic therapeutic viruses. J Clin Invest. 2022:e153437. doi: 10.1172/JCI153437.

Patients with EGFR mutant (exon 20) non-small-cell lung cancer (NSCLC) respond poorly to the tyrosine kinase inhibitors (TKI) osimertinib, dacomitinib, and afatinib. Elamin and colleagues report an open-label phase II study of NSCLC patients treated with the TKI poziotinib. In intention-to-treat analyses, the objective response rate was 32.0% (95% CI, 20.7–45.8). Disease control rate was 84.0% (95% CI, 71.5–92.0). Median progression-free survival was 5.5 months. Poziotinib displayed toxicities similar to other EGFR TKIs: diarrhea, paronychia, and oral mucositis. Preclinical studies in Ba/F3 cell lines showed a direct correlation between poziotinib activity and insertion location, with near-loop insertions being most sensitive. Preclinically, acquired resistance to poziotinib arose through EGFR-dependent mechanisms, including T790M mutations and EGFR-independent mechanisms, such as MET receptor amplification.

Expert Commentary: This study provides evidence that poziotinib achieves objective outcomes in NSCLC patients with EGFR exon 20 alterations, a group who historically showed poor outcomes and responses to current TKIs.

Elamin YY, Robichaux JP, Carter BW, Altan M, Tran H, Gibbons DL, et al. Poziotinib for EGFR exon 20-mutant NSCLC: clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity. Cancer Cell 2022;40:754–67.e6. doi: 10.1016/j.ccell.2022.06.006.

Patients with advanced prostate cancer frequently develop bone metastases, commonly associated with osteoblastic bone-forming lesions. Current approved therapeutic agents for prostate cancer bone metastasis only modestly improve survival. Yu and colleagues showed that prostate cancer–induced aberrant bone formation occurs via an endothelial-to-osteoblast transition (EC-OSB), mediated by tumor-secreted BMP4. Activation of retinoic acid receptors (RAR) by agonists palovarotene or ATRA inhibited BMP4-induced EC-OSB, reducing prostate cancer–induced aberrant bone formation and tumor growth in vivo. EC-OSB is mediated by an interaction of pSmad1 with RAR in the nucleus, and RAR agonists promoted pSmad1 degradation, thereby blocking EC-to-OSB transition. Moreover, plasma levels of tenascin C secreted by EC-OSB cells could be used to monitor treatment response.

Expert Commentary: Activation of retinoic acid receptors by agonists can target prostate cancer–induced aberrant bone formation. These observations suggest that palovarotene or ATRA may reduce tumor-induced bone formation to improve outcomes

Yu G, Corn PG, Shen P, Song JH, Lee Y-C, Lin SC, et al. Retinoic acid receptor activation reduces metastatic prostate cancer bone lesions by blocking the endothelial-to-osteoblast transition. Cancer Res 2022;82:3158–71.

In order to predict therapy responsiveness, prior studies have identified single-cell assays of responsiveness to ex vivo cytokine stimulation as a prognostic feature in some lymphoid and myeloid malignancies. Using customized mass cytometry assays in peripheral blood from patients receiving anti-PD-1 therapies for solid tumors, Boukhaled and colleagues examined the ability of multiple immune cell subsets to respond to type I interferons in vitro. Patients with a lower response to interferon prior to anti-PD1 therapy ultimately exhibited ongoing interferon responsiveness following therapy and longer survival. Subsequent genomic profiling of specific T-cell subsets from the peripheral blood pointed to cell-intrinsic, epigenetic regulation of transcriptional programs in response to interferon as a potential mechanism underlying this differential response and outcome.

Expert Commentary: This work applies an approach to develop an ex vivo predictor of patient response to anti-PD1 therapy in solid tumors. If validated prospectively, such an approach could be useful in identifying patients most likely to benefit from immune checkpoint inhibitors.

Boukhaled G, Gadalla R, Elsaesser H, Abd-Rabbo D, Quevedo R, Yang SYC, et al. Pre-encoded responsiveness to type I interferon in the peripheral immune system defines outcome of PD1 blockade therapy. Nat Immunol 2022;23:1273–83.

Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.