Trametinib Plus Hydroxychloroquine in Two Patients with KRAS-Mutated Chemoresistant Pancreatic Cancer

This case series describes two patients with KRAS-mutated pancreatic adenocarcinoma that had become advanced/metastatic. Neither patient's age nor sex is reported in the source material. Both had previously received chemotherapy that resulted in disease progression before being treated with the experimental regimen described here.

Both patients presented with chemoresistant pancreatic adenocarcinoma, having progressed on prior chemotherapy of unspecified regimen. The disease is described as advanced/metastatic and late-stage; formal TNM staging is not reported in the source.

Diagnosis in both patients was pancreatic adenocarcinoma with a confirmed KRAS mutation; the specific KRAS allele or mutation subtype is not reported. Histologic subtype beyond 'pancreatic adenocarcinoma' is not specified, and no additional biomarker or molecular profiling results are reported.

Beginning in January 2020, both patients received an experimental regimen combining trametinib, a MEK inhibitor, with hydroxychloroquine, used as an autophagy inhibitor, following documented progression on prior chemotherapy. No further detail on dosing, schedule, or treatment duration is provided in the source.

Both patients achieved disease stabilization on the trametinib-hydroxychloroquine combination, described by the authors as clinically meaningful in the context of chemoresistant disease. Outcomes are reported in aggregate for the two-patient cohort; no individual patient-level response, survival, or duration-of-stabilization data are provided.

The observation period spans from January 2020 to the time of publication. Disease stabilization was maintained during this period as reported in aggregate for both patients, without further individual-level follow-up detail, survival data, or information on subsequent treatment changes.

The clinical premise for combining trametinib with hydroxychloroquine in this case rests on two separate strands of evidence rather than a single validated mechanism. First, constitutive RAF-MEK-ERK activation downstream of oncogenic KRAS is an established driver of proliferation and survival in pancreatic adenocarcinoma, and MEK inhibition is understood to suppress this signaling (ev7) — this part of the rationale is reasonably well supported at the level of general PDAC biology, though it does not describe these two patients specifically. Second, PDAC tumor cells are known to depend on autophagy for growth and survival at baseline (ev6), which offers a conceptual reason to co-target autophagy. However, no cited evidence tests whether autophagy is upregulated as a compensatory survival response specifically when MEK signaling is inhibited, nor whether hydroxychloroquine measurably enhances trametinib's antitumor effect in KRAS-mutant PDAC models or patients. The combination's mechanistic rationale is therefore an inference bridging two independently supported but separately studied phenomena, not a demonstrated synergy. In vitro heterogeneity in MEK inhibitor sensitivity across KRAS-mutant PDAC lines (ev9) further indicates that response to MEK-pathway targeting is not uniform across genetic backgrounds, which complicates attributing the stabilization seen in these two patients to any single mechanism, including autophagy inhibition.

This two-patient case series reports disease stabilization on a trametinib-hydroxychloroquine combination in chemoresistant, KRAS-mutant pancreatic adenocarcinoma, framed by the authors as clinically meaningful given the poor prognosis typically associated with this disease state. The available mechanistic evidence supports the general premise that KRAS-driven MAPK signaling is targetable by MEK inhibition in PDAC, and separately supports that PDAC cells rely on autophagy for survival under baseline conditions. Neither of these findings, individually or combined, constitutes direct evidence that autophagy inhibition contributes additively or synergistically to trametinib's effect in this disease context; that specific claim would require studies examining autophagy dynamics under MEK inhibitor exposure, or comparative trials isolating the contribution of hydroxychloroquine, neither of which appears among the verified evidence for this case. The heterogeneity of MEK inhibitor sensitivity documented across KRAS-mutant PDAC cell lines also raises the possibility that the observed stabilization reflects favorable intrinsic pathway dependency in these particular tumors rather than a specific benefit conferred by autophagy inhibition. Given the case reports outcomes only in aggregate for two patients without a comparator arm, distinguishing a genuine drug-combination effect from selection, natural disease course variability, or MEK inhibition alone is not possible on the basis of the information provided.

This is a two-patient case series with outcomes reported only in aggregate; no individual-level response duration, survival, toxicity, or dosing information is available, and there is no control or comparator arm, so causal attribution of stabilization to the specific drug combination cannot be established. The evidence supporting the biological rationale is drawn from a small set of preclinical and review sources that were not designed to test this exact regimen or patient population; the in vitro and animal model findings may not generalize to individual tumor behavior in these patients, whose specific KRAS allele is unknown. This analysis is a secondary synthesis of the reported case and the identified evidence, constrained to the sources verified for this review, and does not represent an independent or exhaustive literature search.

No patient-reported experience, quality-of-life information, or first-person perspective is included in the source material for this case series.