Despite strong data supporting moisturization, barrier repair, and photoprotection, oncologic treatment plans often overlook these interventions. By integrating dermatologic education and skincare maintenance into standard oncologic practice, we can minimize cAEs, foster treatment compliance, and enhance patients' physical comfort and psychosocial well-being. This narrative review synthesizes mechanistic insights, clinical evidence, and practical recommendations for oncologists to champion comprehensive skincare in all cancer patients, whether directly affected by skin issues or not.

Likewise, a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment. Of importance, this combination therapy was well tolerated. In sum, these results should guide the development of new clinical trials that may benefit PDAC patients.

P3, N=590, Recruiting, Revolution Medicines, Inc. | N=420 --> 590

We and others recently discovered that the small molecule PRLX-93936 (PRLX), which was originally developed as an erastin derivative with antitumor activity, is a molecular glue that alters the substrate specificity of the TRIM21 ubiquitin ligase...We also report the discovery of an enhanced molecular glue, MAN-021, and describe its structure. Our findings provide a basis for rational development of next-generation small molecules with enhanced or differentiated activities.

Single-cell profiling reveals dedifferentiation from differentiated states in primary AC into intestinal stem cell and fetal progenitor states in AC-PC, with upregulation of oncogenic signaling pathways. We identify KRASMULTI-ON inhibitor RMC-7977 and the Wnt-targeting tyrosine kinase inhibitor WNTinib as clinically actionable strategies to target AC-PC more effectively.

Recently, RAS(ON) multi-selective inhibitors like RMC-7977, and the investigational agent daraxonrasib, were described that inhibit RAS[GTP] signaling in partnership with cyclophilin A (CYPA). Moreover, two clinical case studies in patients with NRAS-mutated melanoma treated with daraxonrasib demonstrated clear anti-tumor activity in one patient, but progressive disease in another with co-occurring NRAS and MAP2K1 mutations at baseline. These findings support the potential for daraxonrasib in treatment of patients with NRAS-mutated melanoma, and reveal candidate mechanisms of monotherapy resistance, underscoring the need for combination therapies to improve outcomes.

Abcb1a/1b-mediated transport of daraxonrasib across the BBB was validated by oral co-administration of the ABCB1/ABCG2 inhibitor elacridar, resulting in 20-fold increased brain penetration in wild-type mice (P < 0.01). ABCB1 function could limit brain penetration and possibly efficacy of daraxonrasib against brain metastases. Collectively, these preclinical findings may help in optimizing the application of daraxonrasib in clinical settings.

P=N/A, N=0, Available, Revolution Medicines, Inc.

Here, we analyzed paired baseline and end-of-treatment samples from 40 patients treated with the RAS inhibitor daraxonrasib and identified recurrent alterations in 18 cases...We then identified a TCI that targets RAS Y64 mutants and combination therapies to target resistance driven by kinase-dead BRAF. These findings uncover convergent resistance mechanisms that undermine the molecular glue function and offer a mechanistic blueprint for enhancing therapeutic efficacy in RAS-driven malignancies.

Daraxonrasib was associated with treatment-related adverse events of grade 3 or higher in one third of patients with previously treated RAS-mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

KEAP1 loss is associated with reduced response to KRAS inhibitor therapy. We demonstrate that KEAP1 loss-associated resistance can be overcome by pharmacologic inhibition of the KEAP1 loss-induced glutamine dependency, establishing a combination to enhance RAS inhibitor clinical efficacy.

P1, N=392, Recruiting, TheRas, Inc., d/b/a BBOT (BridgeBio Oncology Therapeutics) | N=91 --> 392